RARE DISEASE
Inherited acute myeloid leukemia
Inherited acute myeloid leukemia
Inherited acute myeloid leukemia
Synonyms: Familial AML, Inherited AML, Pure familial AML, Pure familial acute myeloid leukemia
Synonyms: Familial AML, Inherited AML, Pure familial AML, Pure familial acute myeloid leukemia
Synonyms: Familial AML, Inherited AML, Pure familial AML, Pure familial acute myeloid leukemia
Drug discovery
1
drug
With orphan designation
Overview
Inherited acute myeloid leukemia (AML) is a rare malignancy caused by germline mutations (e.g., CEBPA) transmitted in an autosomal dominant pattern, often presenting in younger individuals. Familial AML is characterized by clonal myeloid blast proliferation, with up to 40% of cases linked to predisposing syndromes like Down syndrome or Fanconi anemia. Survival rates (50–65%) exceed sporadic AML, but relapse risk remains high [1][7][9].
Categories: rare genetic diseases, rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
390 drug discovery papers about Inherited acute myeloid leukemia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
390 drug discovery papers about Inherited acute myeloid leukemia, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-11-21 | Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia.
Whereas FMS-like tyrosine kinase-3 (FLT3) inhibitors have significantly improved the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), the emergence of resistance remains as a major challenge. In this study, we applied our recently developed single-cell lineage-tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations. Comparison of the gene expression profiles of these cells revealed transcriptional resistance signatures, including upregulation of GSPT1. Depletion of GSPT1 with CRISPR-Cas9-mediated knockout resulted in increased sensitivity of AML cells to quizartinib treatment. Furthermore, targeting GSPT1 with the small molecule CC-90009 exhibited strong synergistic effects when combined with FLT3 inhibitors in the FLT3-ITD cell lines and primary AML patient samples. In addition, in an FLT3-ITD-positive AML patient-derived xenograft mouse model, the CC-90009 and quizartinib combination showed significantly higher antitumor efficacy and prolonged overall survival compared with either treatment alone. Furthermore, compounds that induced transcriptomic changes opposite to the resistance signatures prompted cells to acquire FLT3 inhibitor-sensitive states. Vistusertib (mTOR inhibitor), linsitinib (IGF1R and INSR inhibitor), and meisoindigo (IGF1R and SRC family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil preexisting transcriptional features of treatment vulnerability in hematologic cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML. Single-cell lineage tracing with ReSisTrace reveals cellular states that prime treatment resistance and identifies approaches to sensitize FLT3-ITD-positive acute myeloid leukemia to FLT3 inhibitors.
2024-10-05 | Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML.
Cop1 encodes a ubiquitin E3 ligase that has been well preserved during evolution in both plants and metazoans. In metazoans, the C/EBP family transcription factors are targets for degradation by Cop1, and this process is regulated by the Tribbles pseudokinase family. Over-expression of Tribbles homolog 1 (Trib1) induces acute myeloid leukemia (AML) via Cop1-dependent degradation of the C/EBPα p42 isoform. Here, we induced rapid growth arrest and granulocytic differentiation of Trib1-expressing AML cells using a Cop1 conditional knockout (KO), which is associated with a transient increase in the C/EBPα p42 isoform. The growth-suppressive effect of Cop1 KO was canceled by silencing of Cebpa and reinforced by exogenous expression of the p42 isoform. Moreover, Cop1 KO improved the survival of recipients transplanted with Trib1-expressing AML cells. We further identified a marked increase in Trib1 protein expression in Cop1 KO, indicating that Trib1 is self-degraded by the Cop1 degradosome. COP1 downregulation also inhibits the proliferation of human AML cells in a TRIB1-dependent manner. Taken together, our results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity, and a novel idea to develop new therapeutics.
2024-07-27 | The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies.
2024-02-20 | DNA methylation analysis using RUNX1-mutated cells reveals association of FLI1 to familial platelet disorder with associated myeloid malignancies caused by a mutation in the transactivation domain of RUNX1
Abstract Background Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1 . It is characterized by thrombocytopenia with platelet dysfunction and a high risk of hematological malignancy development. Although FPDMM is a precursor condition for diseases involving abnormal DNA methylation, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DNA methylation status of FPDMM remains unknown due to a lack of animal models and difficulty in obtaining patient-derived samples. Results Using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. The established FPDMM-mimicking iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. HPCs differentiated from FPDMM-mimicking iPSCs showed DNA methylation patterns distinct from those of wild-type HPCs. Binding motif-enrichment analysis showed the enrichment of ETS transcription factor (TF) motifs in hypermethylated regions, in contrast to the RUNX1 motif. We found that the expression of FLI1 , an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a mutation in the transactivation domain (TAD) of RUNX1. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 in FPDMM-mimicking HPC lines with a RUNX1 TAD mutation restored their Mk differentiation efficiency and hypermethylation status. Conclusion These results suggested that FLI1 is a putative causative TF responsible for differential DNA methylation and defective Mk differentiation in FPDMM-mimicking HPCs in the presence of a mutation in the TAD of RUNX1. Thus, this study provided insights into a part of pathogenesis of FPDMM.
2023-08-16 | CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny.
Aging is associated with an abnormal increase in DNA methylation (DNAm) in human gene promoters, including in bone marrow stem cells. DNAm patterns are further perturbed in hematological malignancies such as acute myeloid leukemia but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNAm spreading beyond the gRNA location. We find that despite a transient delivery system, DNAm is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNAm is maintained in HSPCs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hypermethylated HSPCs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNAm can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNAm on the p15 locus. As such, other aging-associated aberrant DNAm may impact hematopoiesis in vivo.
small molecules
2026-09-28 | [Alantolactone Inhibits AML Cell Proliferation by Enhancing Reactive Oxygen Species and Downregulating the PI3K/Akt Signaling Pathway].
To investigate the effects of alantolactone (AL) on the proliferation and apoptosis of acute myeloid leukemia (AML) cells and its underlying molecular mechanisms. AML cell lines SHI-1 and THP-1 were treated with various concentrations of AL. Cell proliferation capacity was assessed using CCK-8 assay, and cell cycle distribution and apoptosis rate were analyzed by flow cytometry. Intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA fluorescent probe, while the mitochondrial membrane potential (MMP) was evaluated using tetramethylrhodamine ethyl ester (TMRE). Western blot analysis was performed to detect the expression of cell cycle regulatory proteins (CDK4, CDK6), apoptosis-related proteins (cleaved caspase-3, Bax, Bcl-XL, PARP), and proteins involved in the PI3K/Akt signaling pathway. AL significantly inhibited the proliferation of SHI-1 and THP-1 cells in a concentration-dependent (r SHI-1=-0.942 2, r THP-1=-0.882 6) and time-dependent (r SHI-1=-0.979 3, r THP-1=-0.940 0) manner. Meanwhile, AL treatment significantly increased the proportion of cells in G0/G1 phase and apoptosis rate of both SHI-1 and THP-1 cells (P < 0.05), and downregulated the expression of CDK4 and CDK6 (P < 0.05). Additionally, AL significantly upregulated Bax protein expression, downregulated Bcl-XL protein expression, activated caspase-3 and cleaved PARP, thereby promoting cell apoptosis (all P < 0.05). Furthermore, AL treatment significantly elevated intracellular ROS levels and decreased MMP (P < 0.05). Further studies demonstrated that AL could induce programmed cell death in AML cells by inhibiting the activation of the PI3K/Akt signaling pathway. AL may exert anti-leukemic effects by suppressing AML cell proliferation and inducing apoptosis through multiple mechanisms, including inhibition of PI3K/Akt signaling pathway activation, modulation of Bcl-2 family protein expression, and induction of intracellular oxidative stress.
2026-09-22 | Design, synthesis and biological evaluation of a series of new, potent FLT3 PROTAC degraders with rigid linkers.
Fms-like tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase family, is identified as a promising drug target for treatment of acute myeloid leukemia (AML). Here, we designed and synthesized a series of new FLT3 PROTAC degraders by incorporating rigid linkers between gilteritinib and CRBN ligand. Among them, ZLC6-49 and ZLC10-3 were identified as the most potent degraders with DC50 values of 0.74 nM and 1.28 nM, and Dmax values of 85% and 88%, respectively. Mechanistic studies demonstrated that ZLC6-49 and ZLC10-3 induce FLT3 degradation in a cereblon- and proteasome-dependent manner. Furthermore, ZLC6-49 and ZLC10-3 potently inhibit FLT3 downstream signaling, suppress cell proliferation, induce apoptosis and G0/G1-phase arrest in MV4-11 cells.
2026-09-09 | Discovery of highly potent and efficacious Bromodomain and Extra-terminal (BET) degraders with activity against acute myeloid leukemia and triple-negative breast cancer.
Bromodomain and extra-terminal (BET) family proteins are important epigenetic readers and play key roles in cancers, inflammatory diseases, and immune disorders. Current BET inhibitors, which function via an occupancy-driven mechanism, are often hampered by drug resistance and limited efficacy. In this study, a series of novel acetylpyrrole-based BET degraders were designed, synthesized, and evaluated, demonstrating notable antitumor effects in both wild-type and drug-resistant models of acute myeloid leukemia (AML) and triple-negative breast cancer (TNBC). Through structural optimization, 36 (F364) was identified as a potent BRD4 degrader, exhibiting a Dmax of 93.96% and a DC50 of 0.676 nM in the HiBiT assay using HEK293-BRD4-HiBiT-KI cells, slightly superior to the positive control ARV-825. This compound showed strong antiproliferative activity in MV4-11 cells (IC50 = 4.99 nM) and displayed marked efficacy against SHP099-resistant MV4-11 cells (IC50 = 1.62 nM), indicating its potential to overcome resistance to SHP2 inhibitors. Moreover, compound F364 exhibited an IC50 value of 127.87 nM against MDA-MB-231 cells, demonstrating potent antitumor activity toward solid tumor cells. Mechanistic investigations revealed that the degradation process involves the cereblon (CRBN)-mediated proteasomal pathway. In xenograft mouse models using MV4-11 and MDA-MB-231 cells, F364 demonstrated significant antitumor efficacy without observable toxicity. In summary, F364 has been identified as a novel and potent BRD4 degrader, showing promising therapeutic potential for the treatment of acute myeloid leukemia and triple-negative breast cancer.
2026-08-25 | Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation.
Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe²⁺ accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.
2026-07-28 | Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia
Clonal memory, a cellular property inherited across at least two divisions, is a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we develop high-resolution ex vivo tools that track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukaemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restores the clonal memory in division in leukaemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens avenues for tuning cell heterogeneity in healthy and pathological tissues. Healthy blood stem and progenitor cells display synchronised division across generations — a form of clonal memory lost in AML. A bromodomain inhibitor partially restores it, revealing a potential epigenetic vulnerability in leukaemia.
cell therapies
2026-08-11 | Insights to provider practice of germline testing for inherited hematologic malignancy predisposition syndromes to inform hematopoietic stem cell transplantation.
Genomic characteristics play a critical role in the diagnosis, prognosis, and treatment of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Germline profiling of MDS/AML patients who are candidates for allogeneic hematopoietic stem cell transplant (allo-HSCT) can identify inherited monogenic risk mutations, which can guide therapy selection and donor compatibility. Guidelines exist to suggest which allo-HSCT candidates should undergo germline testing. However, the rate of execution of this testing by transplant centers, as well as the perceived practicality of its implementation, has not been evaluated. This study aims to describe the current state of programmatic germline testing for individuals treating MDS/AML patients who are allo-HSCT candidates. Through a cross-sectional survey, we analyzed provider perspectives on genetic counseling services, institutional and current practice guidelines, and insights to germline testing for this patient population. A total of 21 participants completed the survey, most of whom were bone marrow transplant (BMT) coordinators (52.4%) from academic centers (66.7%). While 85.7% of participants reported offering germline evaluation/testing, practices varied widely across centers, with no standardized protocols for patient selection or sample collection. Provider comfort in discussing germline testing implications was variable and often limited, particularly among non-genetics providers, highlighting potential gaps in genetics training. Key barriers included inconsistent guidelines, insurance challenges, and limited provider awareness. Facilitators included collaboration with genetics services-especially genetic counselors-and involvement of BMT physicians and advanced practice providers to support appropriate and timely testing. Standardizing germline testing in HSCT for hematologic malignancies is essential, with sample type and timing as key barriers. We propose integrating routine skin punch biopsy with bone marrow biopsy for patients meeting NCCN criteria for germline testing to streamline cell culturing and sequencing alongside allo-HSCT planning. Involving the BMT team in early referrals and integrating a genetic counselor could improve coordination, address insurance and turnaround challenges, and ensure patients receive timely, actionable genetic insights to their personalized care.
2026-05-08 | CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.
2026-04-01 | Allogeneic CD56+ cell-based immunotherapy in a patient with Fanconi anemia developing acute myeloid leukemia.
Fanconi anemia (FA) is a rare inherited disorder characterized by genomic instability, bone marrow failure, and a markedly increased risk of developing acute myeloid leukemia (AML). The intrinsic hypersensitivity of FA cells to DNA-damaging agents renders conventional chemotherapy particularly toxic and often ineffective. A 31-year-old woman with FA who progressed to AML and failed to achieve remission with standard induction therapy. Bone marrow blasts were initially 10%. As part of a clinical trial, she received CD56+ cell-based immunotherapy after FLAG chemotherapy. She subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor using a CD3+/CD19-depleted graft. Post-transplant, she received additional infusions of CD56+ cells. CD56+ immunotherapy reduced bone marrow blasts from 10 to 3%, enabling successful HSCT. Post-transplant, she remained in complete remission with no detectable minimal residual disease (MRD) at both day +30 and day +90. CD56+ cell-based immunotherapy can effectively decrease the leukemic burden in FA patients with AML, facilitating successful HSCT. This innovative approach may enhance outcomes for high-risk patients and merits further research.
2026-03-21 | Familial acute myeloid leukemia with germline CEBPA mutation in a Syrian family: successfully treated with allogeneic hematopoietic stem cell transplantation
Background Familial acute myeloid leukemia (AML) associated with germline CEBPA mutations is a rare autosomal dominant disorder. Early recognition and genetic testing are essential for diagnosis, management, and donor selection in affected families. Case presentation We report a Syrian family with a confirmed germline CEBPA mutation, the first documented case from Syria and the Middle East. The family includes parents and six children (four boys, two girls). The father previously had AML and achieved complete remission, while one child died from AML at age 10. Two siblings, a 3-year-old boy and girl, developed AML, achieved complete remission after chemotherapy, relapsed, and were successfully treated again to achieve CR2. Both subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from their HLA-matched, CEBPA -negative brother at the Pediatric Stem Cell Transplantation and Cell Therapy Center (HAYAT), the only specialized center in Syria. Conclusion This case highlights the importance of genetic counseling and germline testing in families with inherited AML predisposition. Successful HSCT from a mutation-negative sibling donor can lead to durable remission in pediatric familial AML.
2026-02-05 | Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.
Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34+CD38+ to CD34-CD38+ cells and blocks the differentiation of LSCs (CD34+CD38-) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34-CD38+ to CD34-CD38- cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin-CD127+CD161-CRTH2-CD117- (CD161- ILC1s) that can be generated from umbilical cord blood CD34+ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.
antibodies
2026-06-04 | Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.
The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
2026-06-04 | Extending structural surfaceomics to identify aberrant conformations of tumor surface proteins as potential immunotherapy targets.
The complement of tumor cell surface proteins, or "surfaceome", is a rich source of potential immunotherapy targets. To move beyond expression-based target discovery, we previously described "structural surfaceomics," combining crosslinking mass spectrometry (XL-MS) with surface protein biotinylation to identify conformation-selective targets. In our prior work, we applied this method to a single model of acute myeloid leukemia (AML), identifying active integrin beta-2 as a promising target. Here, we expand structural surfaceomics to identify additional immunotherapy targets and surface protein biology across additional models of AML, multiple myeloma, and prostate cancer, as well as donor peripheral blood mononuclear cells. Utilizing these models and different chemical crosslinkers, we compile an extensive database of 5,209 crosslinks. We characterize both shared and unique crosslink-based features, identifying 1,612 disease model-specific crosslinks, including 212 potentially defining tumor-specific conformations based on distance constraint violations relative to AlphaFold predictions. We further implement a suite of emerging modeling tools to predict tumor-specific protein structures. We probe crosslinking patterns suggesting multiple myeloma-specific CD48 and AML-specific integrin α1/β4 heterodimer conformations. This work establishes a resource for cancer structural biology by implementation of structural surfaceomics. Our findings also point toward more realistic protein design models, potentially enabling systematic detection of targetable cancer-specific epitopes for next-generation immunotherapies.
2025-10-04 | Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.
Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.
2025-07-14 | Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis.
Macrophages in the tumor microenvironment exert potent anti-tumorigenic activity through phagocytosis. Yet therapeutics that enhance macrophage phagocytosis have not improved outcomes in clinical trials for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). To systematically identify regulators of phagocytosis, we performed genome-scale CRISPR knockout screens in human leukemia cells co-cultured with human monocyte-derived macrophages. Surprisingly, we found that whereas the classic "don't eat me" signal CD47 inhibited mouse macrophages, it did not inhibit phagocytosis by human macrophages. In contrast, the O-linked glycosylation and sialylation pathways were strong negative regulators of phagocytosis. In AML, the cell surface O-linked glycoprotein CD43 was the major effector of the O-linked glycosylation and sialylation pathways. Genetic deletion or antibody blockade of CD43 enhanced macrophage phagocytosis. This work highlights the importance of using human platforms to identify immune checkpoints, and nominates CD43 as a glyco-immune regulator of human macrophage phagocytosis.
2024-09-27 | Replication of a GWAS signal near HLA-DQA2 with acute myeloid leukemia using a disease-only cohort and external population-based controls
ABSTRACT Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Its risk factors include rare and highly penetrant somatic mutations. Genome-wide association studies (GWAS) have also identified four common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent datasets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1,865 controls from the population-based cohort CARTaGENE (CaG). Because genotypes were generated using different technologies in the two datasets (e.g. low- vs. high-coverage whole-genome sequencing), we applied stringent quality-control filters to minimize type I errors. We showed using data reduction methods (e.g. principal component analysis [PCA] and uniform manifold approximation and projection [UMAP]) that our approach successfully integrated the Leucegene and CaG genetic data. We replicated the association between cytogenetically normal (CN)-AML and rs3916765, a variant located near HLA-DQA2 (odds ratio [95% confidence interval] = 1.88 [1.21-2.93], P- value=0.005). The effect size of this association was stronger when we restricted the analyses to AML patients with NPM1 mutations (odds ratios >2.35). We found HLA- DOB to be the most significantly upregulated gene in Leucegene participants with the CN-AML protective A-allele at rs3916765. We further found that several HLA class II genes are also differentially expressed albeit at lower statistical significance. Our results confirm that a common genetic variant at the HLA locus associates with AML risk, providing new opportunities to improve disease prognosis and treatment.
other
2026-01-13 | Abstract IA005: Fetal barriers to fusion protein-driven leukemogenesis
Abstract One of the most fascinating aspects of developmental biology is that single-cell blastocysts can expand exponentially to become trillion celled organisms with near-perfect fidelity. In addition to having functional organs and normal appendages, most newborn infants escape neoplasia despite having traversed a stage of life typified by rapidly expanding, highly-stimulated developmental fields. Each cell division cycle creates opportunities for replication errors to occur and propagate, and high proliferation rates magnify this risk. Yet congenital malignancies are exceedingly rare. This raises a fundamental question: What protects the developing fetus from malignancy? Acute myeloid leukemia (AML) illustrates this paradox nicely. A majority of infant and early childhood AML are driven by fusion oncoproteins, expressed as a consequence of translocation mutations that often occur before birth. Infant AML tend to have few additional mutations, implying a low genetic threshold for transformation. Rapid proliferation of hematopoietic stem cells (HSCs) and other progenitors during fetal stages of ontogeny should therefore afford ample opportunity for mutant clones to expand and transform, yet congenital leukemias are exceedingly rare (<10-fold lower than infant leukemias, which are themselves rare). These observations raise the question of whether mechanisms exist to suppress AML initiation during embryogenesis. Using relevant mouse models, we have shown that fetal blood progenitors do indeed actively resist transformation when confronted with recurrent leukemogenic mutations. For example, the MLL::ENL fusion protein reprograms fetal progenitors to create an AML-resistant state that persists even after birth. This protection depends on MLL3, a myeloid tumor suppressor gene that often harbors inherited deleterious variants infant leukemia patients. Inherited variants may therefore mitigate fetal leukemia suppression. As a second example, we have found that NUP98 fusion proteins (e.g., NUP98::HOXA9) convey resistance to AML before birth. NUP98 fusion proteins reprogram the fetal hematopoietic hierarchy to favor non-leukemic erythroid differentiation in situ. This protective developmental reprogramming does not occur in juvenile progenitors, which readily transform. These data illustrate how fetal blood progenitors are hard-wired to differentiate, rather than transform, when they express a fusion oncoprotein. Thus, fusion oncoproteins convey a negative, rather than positive selective pressure. When fusion protein-driven leukemias do arise in utero or in infants, premalignant cells must overcome developmentally restricted failsafe mechanisms so that the fusion protein becomes tolerable at these early ages. Citation Format: Jeff Magee. Fetal barriers to fusion protein-driven leukemogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA005.
2024-06-27 | [Effects of PIM1 Gene on Proliferation, Apoptosis and JAK2/STAT3 Signaling Pathway of Acute Myeloid Leukemia U937 Cells].
To investigate the effects of the serine/threonine kinase family member 1 (PIM1) gene on the proliferation and apoptosis of acute myeloid leukemia (AML) U937 cells, and the regulation effect on Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Bone marrow mononuclear cells from newly diagnosed adult AML patients and patients with iron deficiency anemia were collected and PIM1 mRNA expression was detected by RT-qPCR. AML cell line U937 cells were divided into U937 group (U937 cells were cultured normally), Si-PIM1 group (U937 cells were transfected with low expression adenovirus vector containing PIM1 mRNA), Si-NC group (U937 cells were transfected with low expression adenovirus vector without PIM1 mRNA), coumermycin A1 (CoA1) group (JAK2 activator CoA1 was added to U937 cells at a concentration of 20 μmol/L), and Si-PIM1+CoA1 group (U937 cells were transfected with adenoviral vector containing low expression of PIM1 mRNA and added with CoA1 at a concentration of 20 μmol/L). After culture for 24 h, the expressions of PIM1 mRNA and protein, JAK2/STAT3 pathway, cell cycle and apoptosis-related proteins in U937 cells were detected by RT-qPCR and Western blot, the cell proliferation activity was detected by MTT assay, and flow cytometry was used to detect cell cycle changes and apoptosis rate. The PIM1 mRNA expression level in bone marrow mononuclear cells in AML patients was higher than that in patients with iron deficiency anemia (P < 0.05). Compared with U937 group, PIM1 mRNA and protein, phosphorylated JAK2 (p-JAK2)/JAK2, phosphorylated STAT3 (p-STAT3)/STAT3, Cyclin D1, cyclin-dependent kinase 2 (CDK2) protein, cell proliferation activity, S phase and G 2/M phase proportions were decreased in Si-PIM1 group (all P < 0.05), while p27, Caspase-3 protein, G0/G1 phase proportion and apoptosis rate were increased (all P < 0.05). However, the changes of above indicators in CoA1 group were just opposite to those in Si-PIM1 group, indicating that CoA1 could reverse the effect of Si-PIM1 on U937 cells. There were no significant differences in above indexes of U937 cells between U937 group, Si-PIM1+CoA1 group and Si-NC group (P >0.05). Knockdown of PIM1 gene expression can inhibit U937 cell proliferation and promote apoptosis, in order to alleviate ALM process, which may be related to the inhibition of JAK2/STAT3 pathway activation. PIM1基因对急性髓系白血病U937细胞增殖、凋亡及JAK2/STAT3信号通路的影响. 探讨PIM1基因对急性髓系白血病（AML）U937细胞增殖、凋亡的影响，以及对JAK2/STAT3通路的调控作用。. 收集初诊成人AML患者和单纯缺铁性贫血患者的骨髓单个核细胞，荧光定量PCR检测PIM1 mRNA表达。将AML细胞系U937细胞分为：U937组（U937细胞正常培养）、Si-PIM1组（U937细胞转染含PIM1 mRNA的低表达腺病毒载体）、Si-NC组（U937细胞转染不含PIM1 mRNA的低表达腺病毒载体）、CoA1组（U937细胞中加入浓度为20 μmol/L的JAK2激活剂CoA1）、Si-PIM1+CoA1组（U937细胞转染含PIM1 mRNA低表达的腺病毒载体并加入浓度为20 μmol/L的CoA1）。培养24 h。荧光定量PCR和蛋白印迹法检测U937细胞PIM1 mRNA和蛋白、JAK2/STAT3通路、细胞周期、凋亡相关蛋白表达；噻唑蓝法检测细胞增殖活性；流式细胞术检测细胞周期变化及凋亡率。. AML患者骨髓单个核细胞中PIM1 mRNA表达水平高于单纯缺铁性贫血患者（P < 0.05）。与U937组相比，Si-PIM1组细胞PIM1 mRNA和蛋白、p-JAK2/JAK2、p-STAT3/STAT3、Cyclin D1、CDK2蛋白、细胞增殖活性、S期比例、G2/M期比例降低（均P < 0.05），p27、Caspase-3蛋白、G0/G1期、凋亡率升高（均P < 0.05），而CoA1组上述指标的变化情况与Si-PIM1组正好相反，CoA1可逆转Si-PIM1对U937细胞的作用效果。U937组、Si-PIM1+CoA1组、Si-NC组U937细胞上述指标差异无统计学意义（P >0.05）。. 敲低PIM1基因表达可抑制U937细胞增殖、促进凋亡，缓解ALM进程，且上述作用可能与抑制JAK2/STAT3通路活化有关。.
2024-03-18 | CLPs-miR-103a-2-5p inhibits proliferation and promotes cell apoptosis in AML cells by targeting LILRB3 and Nrf2/HO-1 axis, regulating CD8 + T cell response.
LILRB3, a member of the leukocyte immunoglobulin-like receptor B (LILRB) family, has immunosuppressive functions and directly regulates cancer development, which indicates that LILRB3 is an attractive target for cancer diagnosis and therapy. Novel therapeutic treatments for acute myeloid leukemia (AML) are urgent and important, and RNA therapeutics including microRNAs (miRNAs) could be an effective option. Here, we investigate the role of dysregulated miRNA targeting LILRB3 in the AML microenvironment. Potential miRNAs binding to the 3'-untranslated region (3'-UTR) of the LILRB3 mRNA were predicted by bioinformatics websites. Then, we screened miRNAs targeting LILRB3 by quantitative real-time PCR, and the dual luciferase reporter assay. The expression of LILRB3 and microRNA (miR)-103a-2-5p in AML were determined and then their interactions were also analyzed. In vitro, the effects of miR-103a-2-5p were determined by CCK8, colony formation assay, and transwell assay, while cell apoptosis and cell cycle were analyzed by flow cytometry. Cationic liposomes (CLPs) were used for the delivery of miR-103a-2-5p in the AML mouse model, which was to validate the potential roles of miR-103a-2-5p in vivo. LILRB3 was upregulated in AML cells while miR-103a-2-5p was dramatically downregulated. Thus, a negative correlation was found between them. MiR-103a-2-5p directly targeted LILRB3 in AML cells. Overexpressed miR-103a-2-5p significantly suppressed the mRNA and protein levels of LILRB3, thereby inhibiting AML cell growth and reducing CD8 + T cell apoptosis. In addition, overexpressed miR-103a-2-5p reduced both the relative expression of Nrf2/HO-1 pathway-related proteins and the ratio of GSH/ROS, leading to the excessive intracellular ROS that may promote AML cell apoptosis. In the mouse model, the delivery of miR-103a-2-5p through CLPs could inhibit tumor growth. MiR-103a-2-5p serves as a tumor suppressor that could inhibit AML cell proliferation and promote their apoptosis by downregulating LILRB3 expression, suppressing the Nrf2/HO-1 axis, and reducing the ratio of GSH/ROS. Besides, our findings indicate that miR-103a-2-5p may enhance the CD8 + T cell response by inhibiting LILRB3 expression. Therefore, the delivery of miR-103a-2-5p through CLPs could be useful for the treatment of AML.
2024-02-19 | Propionate promotes ferroptosis and apoptosis through mitophagy and ACSL4-mediated ferroptosis elicits anti-leukemia immunity.
Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid leukemia (AML) remains unclear. Additionally, Acyl-CoA synthetase long chain family member 4 (ACSL4) has been reported to regulate immunity in solid tumors, but there are still many gaps to be filled in AML. Here, we discovered the underlying mechanism of propionate and ACSL4-mediated ferroptosis for immunotherapy. Our results showed that the level of propionate in the AML patients' feces was decreased, which was correlated to gut microbiota dysbiosis. Moreover, we demonstrated that propionate suppressed AML progression both in vivo and in vitro. In mechanism, propionate induced AML cells apoptosis and ferroptosis. The imbalance of reactive oxygen species (ROS) and redox homeostasis induced by propionate caused mitochondrial fission and mitophagy, which enhanced ferroptosis and apoptosis. Furthermore, ACSL4-mediated ferroptosis caused by propionate increased the immunogenicity of AML cells, induced the release of damage-associated molecular patterns (DAMPs), and promoted the maturation of dendritic cells (DCs). The increased level of immunogenicity due to ferroptosis enable propionate-based whole-cell vaccines to activate immunity, thus further facilitating effective killing of AML cells. Collectively, our study uncovers a crucial role for propionate suppresses AML progression by inducing ferroptosis and the potential mechanisms of ACSL4-mediated ferroptosis in the regulation of AML immunity.
2022-04-04 | miR-550-1 functions as a tumor suppressor in acute myeloid leukemia via the hippo signaling pathway.
MicroRNAs (miRNAs) and N6-methyladenosine (m6A) are known to serve as key regulators of acute myeloid leukemia (AML). Our previous microarray analysis indicated miR-550-1 was significantly downregulated in AML. The specific biological roles of miR-550-1 and its indirect interactions and regulation of m6A in AML, however, remain poorly understood. At the present study, we found that miR-550-1 was significantly down-regulated in primary AML samples from human patients, likely owing to hypermethylation of the associated CpG islands. When miR-550-1 expression was induced, it impaired AML cell proliferation both in vitro and in vivo, thus suppressing tumor development. When ectopically expressed, miR-550-1 drove the G0/1 cell cycle phase arrest, differentiation, and apoptotic death of affected cells. We confirmed mechanistically that WW-domain containing transcription regulator-1 (WWTR1) gene was a downstream target of miR-550-1. Moreover, we also identified Wilms tumor 1-associated protein (WTAP), a vital component of the m6A methyltransferase complex, as a target of miR-550-1. These data indicated that miR-550-1 might mediate a decrease in m6A levels via targeting WTAP, which led to a further reduction in WWTR1 stability. Using gain- and loss-of-function approaches, we were able to determine that miR-550-1 disrupted the proliferation and tumorigenesis of AML cells at least in part via the direct targeting of WWTR1. Taken together, our results provide direct evidence that miR-550-1 acts as a tumor suppressor in the context of AML pathogenesis, suggesting that efforts to bolster miR-550-1 expression in AML patients may thus be a viable clinical strategy to improve patient outcomes.
gene therapies
2025-11-21 | Single-Cell Lineage Tracing Uncovers Resistance Signatures and Sensitizing Strategies to FLT3 Inhibitors in Acute Myeloid Leukemia.
Whereas FMS-like tyrosine kinase-3 (FLT3) inhibitors have significantly improved the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), the emergence of resistance remains as a major challenge. In this study, we applied our recently developed single-cell lineage-tracing method ReSisTrace to identify cells that are intrinsically resistant or sensitive to the FLT3 inhibitors midostaurin and quizartinib in AML with FLT3-ITD mutations. Comparison of the gene expression profiles of these cells revealed transcriptional resistance signatures, including upregulation of GSPT1. Depletion of GSPT1 with CRISPR-Cas9-mediated knockout resulted in increased sensitivity of AML cells to quizartinib treatment. Furthermore, targeting GSPT1 with the small molecule CC-90009 exhibited strong synergistic effects when combined with FLT3 inhibitors in the FLT3-ITD cell lines and primary AML patient samples. In addition, in an FLT3-ITD-positive AML patient-derived xenograft mouse model, the CC-90009 and quizartinib combination showed significantly higher antitumor efficacy and prolonged overall survival compared with either treatment alone. Furthermore, compounds that induced transcriptomic changes opposite to the resistance signatures prompted cells to acquire FLT3 inhibitor-sensitive states. Vistusertib (mTOR inhibitor), linsitinib (IGF1R and INSR inhibitor), and meisoindigo (IGF1R and SRC family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to sensitize FLT3-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the ability of ReSisTrace to unveil preexisting transcriptional features of treatment vulnerability in hematologic cancers and elucidate strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-mutated AML. Single-cell lineage tracing with ReSisTrace reveals cellular states that prime treatment resistance and identifies approaches to sensitize FLT3-ITD-positive acute myeloid leukemia to FLT3 inhibitors.
2024-10-05 | Rapid increase of C/EBPα p42 induces growth arrest of acute myeloid leukemia (AML) cells by Cop1 deletion in Trib1-expressing AML.
Cop1 encodes a ubiquitin E3 ligase that has been well preserved during evolution in both plants and metazoans. In metazoans, the C/EBP family transcription factors are targets for degradation by Cop1, and this process is regulated by the Tribbles pseudokinase family. Over-expression of Tribbles homolog 1 (Trib1) induces acute myeloid leukemia (AML) via Cop1-dependent degradation of the C/EBPα p42 isoform. Here, we induced rapid growth arrest and granulocytic differentiation of Trib1-expressing AML cells using a Cop1 conditional knockout (KO), which is associated with a transient increase in the C/EBPα p42 isoform. The growth-suppressive effect of Cop1 KO was canceled by silencing of Cebpa and reinforced by exogenous expression of the p42 isoform. Moreover, Cop1 KO improved the survival of recipients transplanted with Trib1-expressing AML cells. We further identified a marked increase in Trib1 protein expression in Cop1 KO, indicating that Trib1 is self-degraded by the Cop1 degradosome. COP1 downregulation also inhibits the proliferation of human AML cells in a TRIB1-dependent manner. Taken together, our results provide new insights into the role of Trib1/Cop1 machinery in the C/EBPα p42-dependent leukemogenic activity, and a novel idea to develop new therapeutics.
2024-07-27 | The CRISPR-Cas System and Clinical Applications of CRISPR-Based Gene Editing in Hematology with a Focus on Inherited Germline Predisposition to Hematologic Malignancies.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing has begun to transform the treatment landscape of genetic diseases. The history of the discovery of CRISPR/CRISPR-associated (Cas) proteins/single-guide RNA (sgRNA)-based gene editing since the first report of repetitive sequences of unknown significance in 1987 is fascinating, highly instructive, and inspiring for future advances in medicine. The recent approval of CRISPR-Cas9-based gene therapy to treat patients with severe sickle cell anemia and transfusion-dependent β-thalassemia has renewed hope for treating other hematologic diseases, including patients with a germline predisposition to hematologic malignancies, who would benefit greatly from the development of CRISPR-inspired gene therapies. The purpose of this paper is three-fold: first, a chronological description of the history of CRISPR-Cas9-sgRNA-based gene editing; second, a brief description of the current state of clinical research in hematologic diseases, including selected applications in treating hematologic diseases with CRISPR-based gene therapy, preceded by a brief description of the current tools being used in clinical genome editing; and third, a presentation of the current progress in gene therapies in inherited hematologic diseases and bone marrow failure syndromes, to hopefully stimulate efforts towards developing these therapies for patients with inherited bone marrow failure syndromes and other inherited conditions with a germline predisposition to hematologic malignancies.
2024-02-20 | DNA methylation analysis using RUNX1-mutated cells reveals association of FLI1 to familial platelet disorder with associated myeloid malignancies caused by a mutation in the transactivation domain of RUNX1
Abstract Background Familial platelet disorder with associated myeloid malignancies (FPDMM) is an autosomal dominant disease caused by heterozygous germline mutations in RUNX1 . It is characterized by thrombocytopenia with platelet dysfunction and a high risk of hematological malignancy development. Although FPDMM is a precursor condition for diseases involving abnormal DNA methylation, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the DNA methylation status of FPDMM remains unknown due to a lack of animal models and difficulty in obtaining patient-derived samples. Results Using genome editing techniques, we established two lines of human induced pluripotent stem cells (iPSCs) with different FPDMM-mimicking heterozygous RUNX1 mutations. The established FPDMM-mimicking iPSCs showed defective differentiation of hematopoietic progenitor cells (HPCs) and megakaryocytes (Mks), consistent with FPDMM. HPCs differentiated from FPDMM-mimicking iPSCs showed DNA methylation patterns distinct from those of wild-type HPCs. Binding motif-enrichment analysis showed the enrichment of ETS transcription factor (TF) motifs in hypermethylated regions, in contrast to the RUNX1 motif. We found that the expression of FLI1 , an ETS family member, was significantly downregulated in FPDMM-mimicking HPCs with a mutation in the transactivation domain (TAD) of RUNX1. We demonstrated that FLI1 promoted binding-site-directed DNA demethylation, and that overexpression of FLI1 in FPDMM-mimicking HPC lines with a RUNX1 TAD mutation restored their Mk differentiation efficiency and hypermethylation status. Conclusion These results suggested that FLI1 is a putative causative TF responsible for differential DNA methylation and defective Mk differentiation in FPDMM-mimicking HPCs in the presence of a mutation in the TAD of RUNX1. Thus, this study provided insights into a part of pathogenesis of FPDMM.
2023-08-16 | CRISPR/dCas9 DNA methylation editing is heritable during human hematopoiesis and shapes immune progeny.
Aging is associated with an abnormal increase in DNA methylation (DNAm) in human gene promoters, including in bone marrow stem cells. DNAm patterns are further perturbed in hematological malignancies such as acute myeloid leukemia but the physiological significance of such epigenetic changes is unknown. Using epigenetic editing of human stem/progenitor cells (HSPCs), we show that p15 methylation affects hematopoiesis in vivo. We edited the CDKN2B (p15) promoter and ARF (p14) using dCas9-3A3L and observed DNAm spreading beyond the gRNA location. We find that despite a transient delivery system, DNAm is maintained during myeloid differentiation in vitro, and hypermethylation of the p15 promoter reduces gene expression. In vivo, edited human HSPCs can engraft the bone marrow of mice and targeted DNAm is maintained in HSPCs long term. Moreover, epigenetic changes are conserved and inherited in both myeloid and lymphoid lineages. Although the proportion of myeloid (CD33+) and lymphoid (CD19+) cells is unaffected, monocyte (CD14+) populations decreased and granulocytes (CD66b+) increased in mice engrafted with p15 hypermethylated HSPCs. Monocytes derived from p15 hypermethylated HSPCs appear to be activated and show increased inflammatory transcriptional programs. We believe these findings have clinical relevance since we found p15 promoter methylation in the peripheral blood of patients with clonal hematopoiesis. Our study shows DNAm can be targeted and maintained in human HSPCs and demonstrated functional relevance of aberrant DNAm on the p15 locus. As such, other aging-associated aberrant DNAm may impact hematopoiesis in vivo.
small molecules
2026-09-28 | [Alantolactone Inhibits AML Cell Proliferation by Enhancing Reactive Oxygen Species and Downregulating the PI3K/Akt Signaling Pathway].
To investigate the effects of alantolactone (AL) on the proliferation and apoptosis of acute myeloid leukemia (AML) cells and its underlying molecular mechanisms. AML cell lines SHI-1 and THP-1 were treated with various concentrations of AL. Cell proliferation capacity was assessed using CCK-8 assay, and cell cycle distribution and apoptosis rate were analyzed by flow cytometry. Intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA fluorescent probe, while the mitochondrial membrane potential (MMP) was evaluated using tetramethylrhodamine ethyl ester (TMRE). Western blot analysis was performed to detect the expression of cell cycle regulatory proteins (CDK4, CDK6), apoptosis-related proteins (cleaved caspase-3, Bax, Bcl-XL, PARP), and proteins involved in the PI3K/Akt signaling pathway. AL significantly inhibited the proliferation of SHI-1 and THP-1 cells in a concentration-dependent (r SHI-1=-0.942 2, r THP-1=-0.882 6) and time-dependent (r SHI-1=-0.979 3, r THP-1=-0.940 0) manner. Meanwhile, AL treatment significantly increased the proportion of cells in G0/G1 phase and apoptosis rate of both SHI-1 and THP-1 cells (P < 0.05), and downregulated the expression of CDK4 and CDK6 (P < 0.05). Additionally, AL significantly upregulated Bax protein expression, downregulated Bcl-XL protein expression, activated caspase-3 and cleaved PARP, thereby promoting cell apoptosis (all P < 0.05). Furthermore, AL treatment significantly elevated intracellular ROS levels and decreased MMP (P < 0.05). Further studies demonstrated that AL could induce programmed cell death in AML cells by inhibiting the activation of the PI3K/Akt signaling pathway. AL may exert anti-leukemic effects by suppressing AML cell proliferation and inducing apoptosis through multiple mechanisms, including inhibition of PI3K/Akt signaling pathway activation, modulation of Bcl-2 family protein expression, and induction of intracellular oxidative stress.
2026-09-22 | Design, synthesis and biological evaluation of a series of new, potent FLT3 PROTAC degraders with rigid linkers.
Fms-like tyrosine kinase 3 (FLT3), a member of the type III receptor tyrosine kinase family, is identified as a promising drug target for treatment of acute myeloid leukemia (AML). Here, we designed and synthesized a series of new FLT3 PROTAC degraders by incorporating rigid linkers between gilteritinib and CRBN ligand. Among them, ZLC6-49 and ZLC10-3 were identified as the most potent degraders with DC50 values of 0.74 nM and 1.28 nM, and Dmax values of 85% and 88%, respectively. Mechanistic studies demonstrated that ZLC6-49 and ZLC10-3 induce FLT3 degradation in a cereblon- and proteasome-dependent manner. Furthermore, ZLC6-49 and ZLC10-3 potently inhibit FLT3 downstream signaling, suppress cell proliferation, induce apoptosis and G0/G1-phase arrest in MV4-11 cells.
2026-09-09 | Discovery of highly potent and efficacious Bromodomain and Extra-terminal (BET) degraders with activity against acute myeloid leukemia and triple-negative breast cancer.
Bromodomain and extra-terminal (BET) family proteins are important epigenetic readers and play key roles in cancers, inflammatory diseases, and immune disorders. Current BET inhibitors, which function via an occupancy-driven mechanism, are often hampered by drug resistance and limited efficacy. In this study, a series of novel acetylpyrrole-based BET degraders were designed, synthesized, and evaluated, demonstrating notable antitumor effects in both wild-type and drug-resistant models of acute myeloid leukemia (AML) and triple-negative breast cancer (TNBC). Through structural optimization, 36 (F364) was identified as a potent BRD4 degrader, exhibiting a Dmax of 93.96% and a DC50 of 0.676 nM in the HiBiT assay using HEK293-BRD4-HiBiT-KI cells, slightly superior to the positive control ARV-825. This compound showed strong antiproliferative activity in MV4-11 cells (IC50 = 4.99 nM) and displayed marked efficacy against SHP099-resistant MV4-11 cells (IC50 = 1.62 nM), indicating its potential to overcome resistance to SHP2 inhibitors. Moreover, compound F364 exhibited an IC50 value of 127.87 nM against MDA-MB-231 cells, demonstrating potent antitumor activity toward solid tumor cells. Mechanistic investigations revealed that the degradation process involves the cereblon (CRBN)-mediated proteasomal pathway. In xenograft mouse models using MV4-11 and MDA-MB-231 cells, F364 demonstrated significant antitumor efficacy without observable toxicity. In summary, F364 has been identified as a novel and potent BRD4 degrader, showing promising therapeutic potential for the treatment of acute myeloid leukemia and triple-negative breast cancer.
2026-08-25 | Inhibition of nucleoporin 214 depletes leukemia stem cells by promoting heme catabolism and lipid peroxidation.
Chromosomal translocations involving nucleoporin (NUP) loci, such as NUP98 and NUP214, are recurrent in acute myeloid leukemia (AML). However, the intrinsic functions of wild-type nucleoporins in AML remain largely unknown. By screening the NUP family, we identified NUP214 as a frequently overexpressed gene and a critical fitness determinant in leukemia stem cells (LSCs). NUP214 acts as a conserved driver of LSC survival by restricting heme catabolism, limiting Fe²⁺ accumulation, and suppressing lipid peroxidation. Conversely, NUP214 deficiency leads to upregulation of heme oxygenase 1 (HMOX1) and arachidonate 15-lipoxygenase (ALOX15), causing heme exhaustion and excessive lipid peroxidation, which ultimately triggers ferroptosis in LSCs and impairs AML progression. Mechanistically, NUP214 translocates into the nucleoplasm where it blocks Sub1-mediated RNA polymerase II recruitment to repress transcription of the key pro-ferroptotic genes HMOX1 and ALOX15, revealing a non-canonical role beyond its nuclear pore function. Furthermore, we developed the small-molecule compound 0449-b, which acts as a selective NUP214 degrader by recruiting NUP214 to the Cullin5-Rbx2 E3 ligase complex, inducing its neddylation and proteasomal degradation. 0449-b potently triggers LSC ferroptosis and exhibits anti-leukemic activity in vivo, while sparing normal hematopoietic stem cells. Collectively, our findings establish NUP214 as a critical oncoprotein that orchestrates heme metabolism and lipid peroxidation to sustain LSCs, and highlight NUP214-targeted degradation as a promising intervention strategy for AML.
2026-07-28 | Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia
Clonal memory, a cellular property inherited across at least two divisions, is a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we develop high-resolution ex vivo tools that track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukaemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restores the clonal memory in division in leukaemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens avenues for tuning cell heterogeneity in healthy and pathological tissues. Healthy blood stem and progenitor cells display synchronised division across generations — a form of clonal memory lost in AML. A bromodomain inhibitor partially restores it, revealing a potential epigenetic vulnerability in leukaemia.
cell therapies
2026-08-11 | Insights to provider practice of germline testing for inherited hematologic malignancy predisposition syndromes to inform hematopoietic stem cell transplantation.
Genomic characteristics play a critical role in the diagnosis, prognosis, and treatment of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Germline profiling of MDS/AML patients who are candidates for allogeneic hematopoietic stem cell transplant (allo-HSCT) can identify inherited monogenic risk mutations, which can guide therapy selection and donor compatibility. Guidelines exist to suggest which allo-HSCT candidates should undergo germline testing. However, the rate of execution of this testing by transplant centers, as well as the perceived practicality of its implementation, has not been evaluated. This study aims to describe the current state of programmatic germline testing for individuals treating MDS/AML patients who are allo-HSCT candidates. Through a cross-sectional survey, we analyzed provider perspectives on genetic counseling services, institutional and current practice guidelines, and insights to germline testing for this patient population. A total of 21 participants completed the survey, most of whom were bone marrow transplant (BMT) coordinators (52.4%) from academic centers (66.7%). While 85.7% of participants reported offering germline evaluation/testing, practices varied widely across centers, with no standardized protocols for patient selection or sample collection. Provider comfort in discussing germline testing implications was variable and often limited, particularly among non-genetics providers, highlighting potential gaps in genetics training. Key barriers included inconsistent guidelines, insurance challenges, and limited provider awareness. Facilitators included collaboration with genetics services-especially genetic counselors-and involvement of BMT physicians and advanced practice providers to support appropriate and timely testing. Standardizing germline testing in HSCT for hematologic malignancies is essential, with sample type and timing as key barriers. We propose integrating routine skin punch biopsy with bone marrow biopsy for patients meeting NCCN criteria for germline testing to streamline cell culturing and sequencing alongside allo-HSCT planning. Involving the BMT team in early referrals and integrating a genetic counselor could improve coordination, address insurance and turnaround challenges, and ensure patients receive timely, actionable genetic insights to their personalized care.
2026-05-08 | CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.
2026-04-01 | Allogeneic CD56+ cell-based immunotherapy in a patient with Fanconi anemia developing acute myeloid leukemia.
Fanconi anemia (FA) is a rare inherited disorder characterized by genomic instability, bone marrow failure, and a markedly increased risk of developing acute myeloid leukemia (AML). The intrinsic hypersensitivity of FA cells to DNA-damaging agents renders conventional chemotherapy particularly toxic and often ineffective. A 31-year-old woman with FA who progressed to AML and failed to achieve remission with standard induction therapy. Bone marrow blasts were initially 10%. As part of a clinical trial, she received CD56+ cell-based immunotherapy after FLAG chemotherapy. She subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a matched sibling donor using a CD3+/CD19-depleted graft. Post-transplant, she received additional infusions of CD56+ cells. CD56+ immunotherapy reduced bone marrow blasts from 10 to 3%, enabling successful HSCT. Post-transplant, she remained in complete remission with no detectable minimal residual disease (MRD) at both day +30 and day +90. CD56+ cell-based immunotherapy can effectively decrease the leukemic burden in FA patients with AML, facilitating successful HSCT. This innovative approach may enhance outcomes for high-risk patients and merits further research.
2026-03-21 | Familial acute myeloid leukemia with germline CEBPA mutation in a Syrian family: successfully treated with allogeneic hematopoietic stem cell transplantation
Background Familial acute myeloid leukemia (AML) associated with germline CEBPA mutations is a rare autosomal dominant disorder. Early recognition and genetic testing are essential for diagnosis, management, and donor selection in affected families. Case presentation We report a Syrian family with a confirmed germline CEBPA mutation, the first documented case from Syria and the Middle East. The family includes parents and six children (four boys, two girls). The father previously had AML and achieved complete remission, while one child died from AML at age 10. Two siblings, a 3-year-old boy and girl, developed AML, achieved complete remission after chemotherapy, relapsed, and were successfully treated again to achieve CR2. Both subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) from their HLA-matched, CEBPA -negative brother at the Pediatric Stem Cell Transplantation and Cell Therapy Center (HAYAT), the only specialized center in Syria. Conclusion This case highlights the importance of genetic counseling and germline testing in families with inherited AML predisposition. Successful HSCT from a mutation-negative sibling donor can lead to durable remission in pediatric familial AML.
2026-02-05 | Human type-1 innate lymphoid cells control leukemia stem cell differentiation and limit acute myeloid leukemia development.
Innate lymphoid cells (ILCs) are crucial for cancer immunosurveillance. While mouse type 1 ILCs (ILC1s) control acute myeloid leukemia (AML) by targeting leukemia stem cells (LSCs), the role of human ILC1s in AML remains largely undefined. Here, we find that ILC1s in AML patients are impaired, with reduced total ILC1 numbers and diminished function. In contrast, healthy donor (HD) ILC1s-derived TNFα inhibits the leukemic transition from CD34+CD38+ to CD34-CD38+ cells and blocks the differentiation of LSCs (CD34+CD38-) into immunosuppressive, macrophage-like leukemia-supporting cells. HD ILC1-derived IFNγ partially suppresses the differentiation of CD34-CD38+ to CD34-CD38- cells. These combined effects limit human leukemogenesis in vivo. We also identify a human ILC1 subset as Lin-CD127+CD161-CRTH2-CD117- (CD161- ILC1s) that can be generated from umbilical cord blood CD34+ hematopoietic stem cells. This method could provide a reliable source of ILC1s for potential adoptive transfer therapies in AML, offering a therapeutic approach to prolong disease-free survival in AML.
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2026-06-04 | Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting.
The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.
2026-06-04 | Extending structural surfaceomics to identify aberrant conformations of tumor surface proteins as potential immunotherapy targets.
The complement of tumor cell surface proteins, or "surfaceome", is a rich source of potential immunotherapy targets. To move beyond expression-based target discovery, we previously described "structural surfaceomics," combining crosslinking mass spectrometry (XL-MS) with surface protein biotinylation to identify conformation-selective targets. In our prior work, we applied this method to a single model of acute myeloid leukemia (AML), identifying active integrin beta-2 as a promising target. Here, we expand structural surfaceomics to identify additional immunotherapy targets and surface protein biology across additional models of AML, multiple myeloma, and prostate cancer, as well as donor peripheral blood mononuclear cells. Utilizing these models and different chemical crosslinkers, we compile an extensive database of 5,209 crosslinks. We characterize both shared and unique crosslink-based features, identifying 1,612 disease model-specific crosslinks, including 212 potentially defining tumor-specific conformations based on distance constraint violations relative to AlphaFold predictions. We further implement a suite of emerging modeling tools to predict tumor-specific protein structures. We probe crosslinking patterns suggesting multiple myeloma-specific CD48 and AML-specific integrin α1/β4 heterodimer conformations. This work establishes a resource for cancer structural biology by implementation of structural surfaceomics. Our findings also point toward more realistic protein design models, potentially enabling systematic detection of targetable cancer-specific epitopes for next-generation immunotherapies.
2025-10-04 | Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.
Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.
2025-07-14 | Sialylated CD43 is a glyco-immune checkpoint for macrophage phagocytosis.
Macrophages in the tumor microenvironment exert potent anti-tumorigenic activity through phagocytosis. Yet therapeutics that enhance macrophage phagocytosis have not improved outcomes in clinical trials for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). To systematically identify regulators of phagocytosis, we performed genome-scale CRISPR knockout screens in human leukemia cells co-cultured with human monocyte-derived macrophages. Surprisingly, we found that whereas the classic "don't eat me" signal CD47 inhibited mouse macrophages, it did not inhibit phagocytosis by human macrophages. In contrast, the O-linked glycosylation and sialylation pathways were strong negative regulators of phagocytosis. In AML, the cell surface O-linked glycoprotein CD43 was the major effector of the O-linked glycosylation and sialylation pathways. Genetic deletion or antibody blockade of CD43 enhanced macrophage phagocytosis. This work highlights the importance of using human platforms to identify immune checkpoints, and nominates CD43 as a glyco-immune regulator of human macrophage phagocytosis.
2024-09-27 | Replication of a GWAS signal near HLA-DQA2 with acute myeloid leukemia using a disease-only cohort and external population-based controls
ABSTRACT Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Its risk factors include rare and highly penetrant somatic mutations. Genome-wide association studies (GWAS) have also identified four common inherited variants associated with AML risk, but these findings have not yet been confirmed in many independent datasets. Here, we performed a replication study with 567 AML cases from the Leucegene cohort and 1,865 controls from the population-based cohort CARTaGENE (CaG). Because genotypes were generated using different technologies in the two datasets (e.g. low- vs. high-coverage whole-genome sequencing), we applied stringent quality-control filters to minimize type I errors. We showed using data reduction methods (e.g. principal component analysis [PCA] and uniform manifold approximation and projection [UMAP]) that our approach successfully integrated the Leucegene and CaG genetic data. We replicated the association between cytogenetically normal (CN)-AML and rs3916765, a variant located near HLA-DQA2 (odds ratio [95% confidence interval] = 1.88 [1.21-2.93], P- value=0.005). The effect size of this association was stronger when we restricted the analyses to AML patients with NPM1 mutations (odds ratios >2.35). We found HLA- DOB to be the most significantly upregulated gene in Leucegene participants with the CN-AML protective A-allele at rs3916765. We further found that several HLA class II genes are also differentially expressed albeit at lower statistical significance. Our results confirm that a common genetic variant at the HLA locus associates with AML risk, providing new opportunities to improve disease prognosis and treatment.
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2026-01-13 | Abstract IA005: Fetal barriers to fusion protein-driven leukemogenesis
Abstract One of the most fascinating aspects of developmental biology is that single-cell blastocysts can expand exponentially to become trillion celled organisms with near-perfect fidelity. In addition to having functional organs and normal appendages, most newborn infants escape neoplasia despite having traversed a stage of life typified by rapidly expanding, highly-stimulated developmental fields. Each cell division cycle creates opportunities for replication errors to occur and propagate, and high proliferation rates magnify this risk. Yet congenital malignancies are exceedingly rare. This raises a fundamental question: What protects the developing fetus from malignancy? Acute myeloid leukemia (AML) illustrates this paradox nicely. A majority of infant and early childhood AML are driven by fusion oncoproteins, expressed as a consequence of translocation mutations that often occur before birth. Infant AML tend to have few additional mutations, implying a low genetic threshold for transformation. Rapid proliferation of hematopoietic stem cells (HSCs) and other progenitors during fetal stages of ontogeny should therefore afford ample opportunity for mutant clones to expand and transform, yet congenital leukemias are exceedingly rare (<10-fold lower than infant leukemias, which are themselves rare). These observations raise the question of whether mechanisms exist to suppress AML initiation during embryogenesis. Using relevant mouse models, we have shown that fetal blood progenitors do indeed actively resist transformation when confronted with recurrent leukemogenic mutations. For example, the MLL::ENL fusion protein reprograms fetal progenitors to create an AML-resistant state that persists even after birth. This protection depends on MLL3, a myeloid tumor suppressor gene that often harbors inherited deleterious variants infant leukemia patients. Inherited variants may therefore mitigate fetal leukemia suppression. As a second example, we have found that NUP98 fusion proteins (e.g., NUP98::HOXA9) convey resistance to AML before birth. NUP98 fusion proteins reprogram the fetal hematopoietic hierarchy to favor non-leukemic erythroid differentiation in situ. This protective developmental reprogramming does not occur in juvenile progenitors, which readily transform. These data illustrate how fetal blood progenitors are hard-wired to differentiate, rather than transform, when they express a fusion oncoprotein. Thus, fusion oncoproteins convey a negative, rather than positive selective pressure. When fusion protein-driven leukemias do arise in utero or in infants, premalignant cells must overcome developmentally restricted failsafe mechanisms so that the fusion protein becomes tolerable at these early ages. Citation Format: Jeff Magee. Fetal barriers to fusion protein-driven leukemogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr IA005.
2024-06-27 | [Effects of PIM1 Gene on Proliferation, Apoptosis and JAK2/STAT3 Signaling Pathway of Acute Myeloid Leukemia U937 Cells].
To investigate the effects of the serine/threonine kinase family member 1 (PIM1) gene on the proliferation and apoptosis of acute myeloid leukemia (AML) U937 cells, and the regulation effect on Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. Bone marrow mononuclear cells from newly diagnosed adult AML patients and patients with iron deficiency anemia were collected and PIM1 mRNA expression was detected by RT-qPCR. AML cell line U937 cells were divided into U937 group (U937 cells were cultured normally), Si-PIM1 group (U937 cells were transfected with low expression adenovirus vector containing PIM1 mRNA), Si-NC group (U937 cells were transfected with low expression adenovirus vector without PIM1 mRNA), coumermycin A1 (CoA1) group (JAK2 activator CoA1 was added to U937 cells at a concentration of 20 μmol/L), and Si-PIM1+CoA1 group (U937 cells were transfected with adenoviral vector containing low expression of PIM1 mRNA and added with CoA1 at a concentration of 20 μmol/L). After culture for 24 h, the expressions of PIM1 mRNA and protein, JAK2/STAT3 pathway, cell cycle and apoptosis-related proteins in U937 cells were detected by RT-qPCR and Western blot, the cell proliferation activity was detected by MTT assay, and flow cytometry was used to detect cell cycle changes and apoptosis rate. The PIM1 mRNA expression level in bone marrow mononuclear cells in AML patients was higher than that in patients with iron deficiency anemia (P < 0.05). Compared with U937 group, PIM1 mRNA and protein, phosphorylated JAK2 (p-JAK2)/JAK2, phosphorylated STAT3 (p-STAT3)/STAT3, Cyclin D1, cyclin-dependent kinase 2 (CDK2) protein, cell proliferation activity, S phase and G 2/M phase proportions were decreased in Si-PIM1 group (all P < 0.05), while p27, Caspase-3 protein, G0/G1 phase proportion and apoptosis rate were increased (all P < 0.05). However, the changes of above indicators in CoA1 group were just opposite to those in Si-PIM1 group, indicating that CoA1 could reverse the effect of Si-PIM1 on U937 cells. There were no significant differences in above indexes of U937 cells between U937 group, Si-PIM1+CoA1 group and Si-NC group (P >0.05). Knockdown of PIM1 gene expression can inhibit U937 cell proliferation and promote apoptosis, in order to alleviate ALM process, which may be related to the inhibition of JAK2/STAT3 pathway activation. PIM1基因对急性髓系白血病U937细胞增殖、凋亡及JAK2/STAT3信号通路的影响. 探讨PIM1基因对急性髓系白血病（AML）U937细胞增殖、凋亡的影响，以及对JAK2/STAT3通路的调控作用。. 收集初诊成人AML患者和单纯缺铁性贫血患者的骨髓单个核细胞，荧光定量PCR检测PIM1 mRNA表达。将AML细胞系U937细胞分为：U937组（U937细胞正常培养）、Si-PIM1组（U937细胞转染含PIM1 mRNA的低表达腺病毒载体）、Si-NC组（U937细胞转染不含PIM1 mRNA的低表达腺病毒载体）、CoA1组（U937细胞中加入浓度为20 μmol/L的JAK2激活剂CoA1）、Si-PIM1+CoA1组（U937细胞转染含PIM1 mRNA低表达的腺病毒载体并加入浓度为20 μmol/L的CoA1）。培养24 h。荧光定量PCR和蛋白印迹法检测U937细胞PIM1 mRNA和蛋白、JAK2/STAT3通路、细胞周期、凋亡相关蛋白表达；噻唑蓝法检测细胞增殖活性；流式细胞术检测细胞周期变化及凋亡率。. AML患者骨髓单个核细胞中PIM1 mRNA表达水平高于单纯缺铁性贫血患者（P < 0.05）。与U937组相比，Si-PIM1组细胞PIM1 mRNA和蛋白、p-JAK2/JAK2、p-STAT3/STAT3、Cyclin D1、CDK2蛋白、细胞增殖活性、S期比例、G2/M期比例降低（均P < 0.05），p27、Caspase-3蛋白、G0/G1期、凋亡率升高（均P < 0.05），而CoA1组上述指标的变化情况与Si-PIM1组正好相反，CoA1可逆转Si-PIM1对U937细胞的作用效果。U937组、Si-PIM1+CoA1组、Si-NC组U937细胞上述指标差异无统计学意义（P >0.05）。. 敲低PIM1基因表达可抑制U937细胞增殖、促进凋亡，缓解ALM进程，且上述作用可能与抑制JAK2/STAT3通路活化有关。.
2024-03-18 | CLPs-miR-103a-2-5p inhibits proliferation and promotes cell apoptosis in AML cells by targeting LILRB3 and Nrf2/HO-1 axis, regulating CD8 + T cell response.
LILRB3, a member of the leukocyte immunoglobulin-like receptor B (LILRB) family, has immunosuppressive functions and directly regulates cancer development, which indicates that LILRB3 is an attractive target for cancer diagnosis and therapy. Novel therapeutic treatments for acute myeloid leukemia (AML) are urgent and important, and RNA therapeutics including microRNAs (miRNAs) could be an effective option. Here, we investigate the role of dysregulated miRNA targeting LILRB3 in the AML microenvironment. Potential miRNAs binding to the 3'-untranslated region (3'-UTR) of the LILRB3 mRNA were predicted by bioinformatics websites. Then, we screened miRNAs targeting LILRB3 by quantitative real-time PCR, and the dual luciferase reporter assay. The expression of LILRB3 and microRNA (miR)-103a-2-5p in AML were determined and then their interactions were also analyzed. In vitro, the effects of miR-103a-2-5p were determined by CCK8, colony formation assay, and transwell assay, while cell apoptosis and cell cycle were analyzed by flow cytometry. Cationic liposomes (CLPs) were used for the delivery of miR-103a-2-5p in the AML mouse model, which was to validate the potential roles of miR-103a-2-5p in vivo. LILRB3 was upregulated in AML cells while miR-103a-2-5p was dramatically downregulated. Thus, a negative correlation was found between them. MiR-103a-2-5p directly targeted LILRB3 in AML cells. Overexpressed miR-103a-2-5p significantly suppressed the mRNA and protein levels of LILRB3, thereby inhibiting AML cell growth and reducing CD8 + T cell apoptosis. In addition, overexpressed miR-103a-2-5p reduced both the relative expression of Nrf2/HO-1 pathway-related proteins and the ratio of GSH/ROS, leading to the excessive intracellular ROS that may promote AML cell apoptosis. In the mouse model, the delivery of miR-103a-2-5p through CLPs could inhibit tumor growth. MiR-103a-2-5p serves as a tumor suppressor that could inhibit AML cell proliferation and promote their apoptosis by downregulating LILRB3 expression, suppressing the Nrf2/HO-1 axis, and reducing the ratio of GSH/ROS. Besides, our findings indicate that miR-103a-2-5p may enhance the CD8 + T cell response by inhibiting LILRB3 expression. Therefore, the delivery of miR-103a-2-5p through CLPs could be useful for the treatment of AML.
2024-02-19 | Propionate promotes ferroptosis and apoptosis through mitophagy and ACSL4-mediated ferroptosis elicits anti-leukemia immunity.
Short-chain fatty acids (SCFAs), particularly propionate and butyrate, have been reported in many cancers. However, the relationship between propionate and acute myeloid leukemia (AML) remains unclear. Additionally, Acyl-CoA synthetase long chain family member 4 (ACSL4) has been reported to regulate immunity in solid tumors, but there are still many gaps to be filled in AML. Here, we discovered the underlying mechanism of propionate and ACSL4-mediated ferroptosis for immunotherapy. Our results showed that the level of propionate in the AML patients' feces was decreased, which was correlated to gut microbiota dysbiosis. Moreover, we demonstrated that propionate suppressed AML progression both in vivo and in vitro. In mechanism, propionate induced AML cells apoptosis and ferroptosis. The imbalance of reactive oxygen species (ROS) and redox homeostasis induced by propionate caused mitochondrial fission and mitophagy, which enhanced ferroptosis and apoptosis. Furthermore, ACSL4-mediated ferroptosis caused by propionate increased the immunogenicity of AML cells, induced the release of damage-associated molecular patterns (DAMPs), and promoted the maturation of dendritic cells (DCs). The increased level of immunogenicity due to ferroptosis enable propionate-based whole-cell vaccines to activate immunity, thus further facilitating effective killing of AML cells. Collectively, our study uncovers a crucial role for propionate suppresses AML progression by inducing ferroptosis and the potential mechanisms of ACSL4-mediated ferroptosis in the regulation of AML immunity.
2022-04-04 | miR-550-1 functions as a tumor suppressor in acute myeloid leukemia via the hippo signaling pathway.
MicroRNAs (miRNAs) and N6-methyladenosine (m6A) are known to serve as key regulators of acute myeloid leukemia (AML). Our previous microarray analysis indicated miR-550-1 was significantly downregulated in AML. The specific biological roles of miR-550-1 and its indirect interactions and regulation of m6A in AML, however, remain poorly understood. At the present study, we found that miR-550-1 was significantly down-regulated in primary AML samples from human patients, likely owing to hypermethylation of the associated CpG islands. When miR-550-1 expression was induced, it impaired AML cell proliferation both in vitro and in vivo, thus suppressing tumor development. When ectopically expressed, miR-550-1 drove the G0/1 cell cycle phase arrest, differentiation, and apoptotic death of affected cells. We confirmed mechanistically that WW-domain containing transcription regulator-1 (WWTR1) gene was a downstream target of miR-550-1. Moreover, we also identified Wilms tumor 1-associated protein (WTAP), a vital component of the m6A methyltransferase complex, as a target of miR-550-1. These data indicated that miR-550-1 might mediate a decrease in m6A levels via targeting WTAP, which led to a further reduction in WWTR1 stability. Using gain- and loss-of-function approaches, we were able to determine that miR-550-1 disrupted the proliferation and tumorigenesis of AML cells at least in part via the direct targeting of WWTR1. Taken together, our results provide direct evidence that miR-550-1 acts as a tumor suppressor in the context of AML pathogenesis, suggesting that efforts to bolster miR-550-1 expression in AML patients may thus be a viable clinical strategy to improve patient outcomes.
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Drug Discovery Landscape
1 orphan drug designation for Inherited acute myeloid leukemia.
1 orphan drug designation for Inherited acute myeloid leukemia.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
macrocyclic, ATP-competitive small molecule inhibitor of CDC-like kinase 1/2/4 (CLK1/2/4) | small molecules | FDA | BlossomHill Therapeutics |
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