RARE DISEASE
Acute leukemia of ambiguous lineage
Acute leukemia of ambiguous lineage
Acute leukemia of ambiguous lineage
Synonyms: Acute leukemia of indeterminate lineage, Hybrid acute leukemia, Mixed lineage acute leukemia
Synonyms: Acute leukemia of indeterminate lineage, Hybrid acute leukemia, Mixed lineage acute leukemia
Synonyms: Acute leukemia of indeterminate lineage, Hybrid acute leukemia, Mixed lineage acute leukemia
Drug discovery
1
drug
With orphan designation
Overview
Acute leukemia of ambiguous lineage (ALAL) encompasses rare, high-risk leukemias lacking definitive myeloid or lymphoid differentiation. Classified into mixed-phenotype acute leukemia (MPAL) and acute undifferentiated leukemia (AUL), these malignancies present diagnostic challenges due to immunophenotypic heterogeneity and frequent cytogenetic abnormalities like BCR-ABL1 or KMT2A rearrangements [1][2][6]. Prognosis remains poor, particularly in adults, with high relapse rates despite aggressive therapies [2][10].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
579 drug discovery papers about Acute leukemia of ambiguous lineage, with 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
579 drug discovery papers about Acute leukemia of ambiguous lineage, with 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-08-15 | TA-TMA occurring after sequential CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation: a case report.
Currently, CAR-T cell therapy bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a pivotal therapeutic strategy for refractory/relapsed hematologic malignancies. Sequential therapy with CD7 chimeric antigen receptor T (CAR-T) cells combined with allo-HSCT provides a novel therapeutic approach for T-lymphoid malignancies, CD7-highly expressed acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). This strategy circumvents the toxicities of conventional myeloablative conditioning chemotherapy and immunosuppressive agents, while achieving tumor eradication, hematopoietic reconstitution, and prevention of graft-versus-host disease (GVHD). Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare but life-threatening complication following allo-HSCT, associated with elevated non-relapse mortality (NRM). This article reports a case of early-onset TA-TMA in a patient with MPAL after CD7 CAR-T bridging to allo-HSCT. This study aims to enhance clinicians' awareness of the diagnosis and management of TA-TMA following CAR-T bridging to allo-HSCT, provide a reference for early identification and timely intervention, and further improve patient outcomes.
2026-04-16 | Durable deep molecular response via CD19 chimeric antigen receptor T-cell therapy combined with a third-generation tyrosine kinase inhibitor in acute leukemia of ambiguous lineage with the Philadelphia chromosome: a potential strategy for transplant-ineligible patients.
Not available.
2026-03-31 | Exploring mixed phenotype acute leukemia: Clinical, immunophenotypic, cytogenetic, and prognostic insights from a tertiary care center.
Mixed-phenotype acute leukemias (MPALs) are a rare and aggressive group of leukemias, accounting for approximately 2%-5% of all leukemia cases. MPAL is characterized by the expression of markers from more than one hematopoietic lineage, either myeloid and lymphoid, which can be identified through flow cytometry immunophenotyping. This study aims to describe the clinicopathological, immunophenotypic, and cytogenetic features of a cohort of 27 patients diagnosed with MPAL at our institution. We conducted a retrospective analysis of 27 consecutive MPAL cases diagnosed between January 2016 and September 2020 at our tertiary care center. All cases were classified based on the WHO 2016 diagnostic criteria using flow cytometry for immunophenotyping. Available cytogenetic and molecular data were also analyzed. Among 1622 acute leukemia cases diagnosed during the study period, 27 (1.7%) fulfilled the diagnostic criteria for MPAL. The cohort had a male-to-female ratio of 4.4:1, with a median age of 21 years. The cases were classified as B/myeloid (n = 16) and T/myeloid (n = 11). Cytogenetic data were available for 18 patients, of which 7 cases had a normal karyotype. The remaining cases displayed various abnormalities, including trisomy 8, t(8:14)(q11.2;q32), and t(9;22). The induction mortality rate was notably high at 54%, primarily due to infections and poor general condition of patients at presentation. No significant survival difference was observed between B/myeloid and T/myeloid subgroups. MPAL remains a rare and challenging leukemia to diagnose and treat, requiring precise immunophenotypic analysis for accurate classification. MPAL constituted a small proportion (1.7%) of acute leukemias in our cohort and was associated with extremely poor outcomes, reflected by the very high induction mortality (54%) and median survival of only 1 month. Survival did not differ significantly between B/myeloid and T/myeloid subtypes, underscoring the uniformly adverse prognosis. These findings highlight the urgent need for improved supportive care, early recognition, and integration of novel strategies-including timely allogeneic transplantation-to improve outcomes in this clinically challenging and prognostically adverse entity.
2026-03-28 | The Efficiency of Allotransplant in a Case of Acute Biphenotypic Myeloid and B-Lymphoid Leukemia (MPAL Myelo/B NOS) That Presented Concurrently with a Mediastinal Granulocytic Sarcoma Co-Expressing Lymphoid Markers Complicated by Cardiac Tamponade.
Background and Clinical Significance: Mixed-phenotype acute leukemia (MPAL) is a rare hematologic malignancy characterized by the co-expression of myeloid and lymphoid markers and is associated with poor prognosis. Myeloid sarcoma (MS), particularly in the mediastinum, is an uncommon extramedullary manifestation and is rarely reported in association with MPAL. Case Presentation: We report a rare case of mediastinal MS with biphenotypic features and pericardial extension occurring concurrently with MPAL, highlighting diagnostic challenges, therapeutic strategies, and long-term outcomes. We describe the clinical course, diagnostic workup, treatment, and follow-up of a 21-year-old woman who presented with cardiac tamponade secondary to a mediastinal mass. Histopathology and immunophenotyping established the diagnosis of mediastinal MS associated with MPAL (B/myeloid, NOS). Management included surgical cytoreduction, intensive induction chemotherapy, and consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. Fertility preservation with oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation was performed prior to conditioning. A focused literature review of MPAL cases with extramedullary involvement was conducted. The patient achieved complete remission following induction therapy and underwent allo-HSCT. Despite the historically poor prognosis of mediastinal MS and MPAL, she remains in sustained complete remission 13 years after diagnosis. A literature review identified only eight reported cases of MPAL with extramedullary disease, with mediastinal involvement described in a single case and allo-HSCT performed in only two patients. Conclusions: This case illustrates a rare presentation of MPAL with mediastinal myeloid sarcoma and cardiac tamponade, demonstrating that aggressive multimodal therapy including allo-HSCT may achieve durable remission even in high-risk presentations. Early multidisciplinary management and consideration of fertility preservation are essential in young patients.
2026-02-25 | Allogeneic Hematopoietic Stem Cell Transplantation for Children With Mixed Phenotype Acute Leukemia: A Single-Center Retrospective Study.
Mixed phenotype acute leukemia (MPAL) represents an uncommon but heterogenous disease, often posing both a diagnostic and therapeutic challenge. The purpose of this retrospective study was to analyze the overall survival, event-free survival, and severity of associated complications after allo-HSCT in children with MPAL, and provide feasible recommendations for the treatment of MPAL patients. We retrospectively analyzed a total of 14 pediatric patients with MPAL who received allo-HSCT at our center between January 2010 and June 2024. In terms of immunophenotype, coexpression of myeloid and B-lymphoid antigens was observed in 10 patients (71.4%), and myeloid and T-lymphoid antigens in 4 (28.6%). Chromosomal abnormalities were found in 8 patients (57.1%) and BCR/ABL(+) was the most common fusion gene (3/14; 21.4%). All 14 patients underwent allo-HSCT after achieving the CR1 (78.6% with MRD-negative status pretransplantation). Among the 14 transplanted children, the OS rate was 92.9% and the EFS rate was 85.7%. No significant difference in OS, EFS, and CIR rates between children with Haplo-HSCT and those with MSD-HSCT (P>0.05). The rate of acute GVHD was 57.1% (8/14), and the rate of chronic GVHD was 71.4%, of which 90% were assessed as mild cGVHD, with the skin being the most common organ involved in cGVHD. Only one patient developed TA-TMA and died from transplant-related complications. The children with MPAL who received allo-HSCT after MRD-negative CR often had a favorable disease control. Compared with patients receiving conventional chemotherapy, pediatric patients who received allo-HSCT showed a significant improvement in OS, EFS, and CIR rates. Although the incidence of cGVHD was relatively high, most of them were assessed as mild with no significant impact on daily activities.
small molecules
2026-09-01 | The Fanconi anemia pathway restrains MLL-rearranged leukemogenesis through suppressing non-homologous end joining-mediated genomic instability
Mixed lineage leukemia (MLL) rearrangements drive approximately 10% of acute leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Individuals with Fanconi anemia (FA), a hereditary DNA damage repair (DDR) disorder, are at markedly increased risk of AML, yet the interplay between FA deficiency and MLL-rearranged (MLL-r) leukemia remains unclear. Using murine models and human MLL-r leukemia cells, we show that the FA pathway suppresses leukemogenesis by limiting error-prone non-homologous end joining (NHEJ)-mediated genomic instability. Loss of FA components accelerates leukemia development, promotes leukemic stem cell expansion, and increases DNA damage through hyperactive NHEJ. Pharmacological NHEJ inhibition selectively impairs the survival of FA-deficient MLL-r leukemia cells, revealing a synthetic lethal vulnerability. Consistent with these findings, reduced FA pathway gene expression in patient samples correlates with poor prognosis and increased sensitivity to NHEJ inhibition. These findings identify NHEJ blockade as a promising targeted therapeutic strategy for high-risk MLL-r leukemia. Mutations in the Fanconi anemia (FA) DNA repair genes predispose to leukemia and bone marrow failure. Here, the authors discover that the FA pathway controls MLL-rearranged leukemia progression via blocking nonhomologous end joining-mediated genomic instability.
2026-08-28 | Venetoclax with azacitidine and dexamethasone: Non-cytotoxic induction therapy for T-cell leukemia and mixed-phenotype leukemia.
T-lineage acute leukemias are aggressive malignancies for which treatment options are limited. This study evaluated the efficacy and safety of a non-cytotoxic regimen combining venetoclax, azacitidine, and dexamethasone (VAD) as first-line induction therapy for T-cell acute lymphoblastic leukemia (T-ALL) and T/myeloid mixed-phenotype acute leukemia (T-Myeloid MPAL). We retrospectively analyzed the clinical parameters and survival data of 11 patients with newly-diagnosed T-ALL or T-Myeloid MPAL who received the VAD regimen. The complete remission (CR) rate and adverse events were assessed. Kaplan-Meier curves were constructed to evaluate survival outcomes. Among 11 patients (7 with early T-cell precursor [ETP] ALL, 2 with T-Myeloid MPAL, and 2 with non-ETP T-ALL), the overall CR rate after one cycle of VAD therapy was 90.9%, with 45.5% achieving measurable residual disease (MRD) negativity by flow cytometry. The historically poor-prognosis ETP-ALL subgroup showed an 85.7% CR rate (6/7), while both T-Myeloid MPAL cases attained MRD negativity. No tumor lysis syndrome or treatment-related mortality occurred. Over a median follow-up of 358 days, all 5 patients who received transplantations remained relapse-free. The VAD regimen demonstrated a high response rate and favorable safety, enabling effective transplantation bridging with avoidance of conventional cytotoxic therapy.
2026-06-26 | Mixed Phenotype Acute Leukemia: Lineage Assignment, Immunophenotypic Classification and Genetic Insights.
Mixed phenotype acute leukemia (MPAL) is a rare and biologically heterogeneous category characterized by discrete admixed populations of myeloid and lymphoid blasts (bilineal or mixed lineage) or with coexpression of lymphoid and myeloid markers in a single blast population (biphenotypic or mixed phenotype). Despite advances in diagnostic criteria, MPAL remains a significant diagnostic and therapeutic challenge due to its immunophenotypic complexity and genetic diversity. Accurate classification relies heavily on multiparameter flow cytometry immunophenotyping, integrated with cytogenetic and molecular studies. The current World Health Organization classification and International Consensus Classification recognize specific genetic subtypes, including MPAL with t(9;22)(q34.1;q11.2)/BCR::ABL1 and MPAL with KMT2A rearrangement, reflecting the increasing importance of genomic profiling in disease characterization. Recent genomic studies have revealed additional recurrent alterations involving transcription factors, epigenetic regulators, signaling pathways, and lineage-specifying genes, including ZNF384 rearrangements, BCL11B alterations, mutations involving PHF6, WT1, FLT3, and RUNX1, and mutations affecting chromatin remodeling and cytokine signaling pathways. Importantly, distinct genetic lesions appear to correlate with specific immunophenotypic patterns, suggesting biologically meaningful disease subsets and providing insights into mechanisms of lineage plasticity and leukemogenesis. This review summarizes the current understanding of the immunophenotypic and genetic landscape of MPAL, emphasizing the integration of morphologic, immunophenotypic, cytogenetic, and molecular findings into diagnosis and subclassification.
2026-06-12 | Effect of the Proteasome Inhibitor, Bortezomib, on Histone Modifications in Human Leukemic Cell Lines
Histone-modifying enzymes and histone post-translational modifications (PTMs) play key roles in the organization (euchromatin versus heterochromatin) and function (active versus silenced genes) of chromatin. The abundance and activity of these enzymes, along with their associated histone PTMs, are often altered in cancer cells, leading to deregulated gene expression. The expression of the KMT2A-MLLT3 protein, resulting from a chromosomal translocation in mixed-lineage leukemia (MLL), a subtype of acute myeloid leukemia, augments transcription elongation, promoting the expression of HOXA9 and MEIS1, genes that play critical roles in MLL development. Bortezomib, a proteasome inhibitor, has been effective in treating various cancers. In this study, we compared the impact of bortezomib on histone PTMs in the MLL cell line MOLM-13 and the chronic myeloid leukemic (CML) cell line K562. We report that MOLM-13 had a greater level of histone H2B monoubiquitinated at lysine 120 (H2BK120ub) and histone H3 dimethylated at lysine 79 (H3K79me2) (modifications involved in elongation) and similar levels of histone H2A monoubiquitinated at lysine 119 (H2AK119ub). Bortezomib treatment resulted in significant reductions in H2BK120ub and H2AK119ub levels, the loss of FAcilitates Chromatin Transcription (FACT) chromatin association in both cell lines, and the reduced transcript levels of genes involved in the development of MLL.
2026-06-06 | Genetic Landscape of Acute Leukemia of Ambiguous Lineage: A Single Cancer Center Experience.
Acute leukemias of ambiguous lineage (ALALs) are rare acute leukemias with poor prognosis, encompassing acute undifferentiated leukemia and mixed-phenotype acute leukemia. The fifth edition of the World Health Organization classification of hematolymphoid tumors recommends excluding ALAL cases with myelodysplasia-associated mutations and/or cytogenetic abnormalities from classification as acute undifferentiated leukemia or mixed-phenotype acute leukemia, instead categorizing them as acute myeloid leukemia with myelodysplasia (AML-MR; hereafter referred to as AML-MR/ALAL), a distinct entity with limited genetic and clinical characterization to date. In this study, the genetic and clinical characteristics of AML-MR/ALAL were investigated in comparison with those of ALAL and AML-MR. RUNX1 (7/11; 63.6%), WT1 (3/11; 27.3%), DNMT3A (2/11; 18.2%), TET2 (2/11; 18.2%), BCORL1 (2/11; 18.2%), and TP53 (2/11; 18.2%) were identified as the most frequently mutated genes in AML-MR/ALAL. Moreover, AML-MR/ALAL shared genetic features with AML-MR and was distinct from ALAL. Although no significant difference in overall survival was observed between AML-MR/ALAL and ALAL, patients with AML-MR/ALAL showed a trend toward worse prognosis. In summary, these findings suggest that AML-MR/ALAL may be more appropriately classified as AML-MR; however, validation in larger cohorts is required.
antibodies
2025-05-01 | Pre-transplant blinatumomab and/or inotuzumab ozogamicin therapy for relapsed/refractory acute lymphoblastic and B/myeloid mixed phenotype acute leukemia in adults.
Real-world data on blinatumomab (BLI) and inotuzumab ozogamicin (INO) for relapsed or refractory B-acute lymphoblastic leukemia (RR-ALL) before hematopoietic stem cell transplantation (HCT) are limited. To compare the efficacy of salvage therapy with BLI and/or INO and conventional chemotherapy as a bridge to HCT, we retrospectively evaluated patients with RR-ALL who underwent first HCT at our institute between 2004 and 2023. Based on whether they had received salvage therapy with BLI and/or INO, 70 recipients were divided into a BLI/INO (n = 22) and a control group (n = 48). The complete remission (CR) rate before HCT was higher in the BLI/INO group than in the control group (77.3 % vs. 35.4 %, p = 0.002). Two years after the first HCT, the overall survival (OS) and disease-free survival (DFS) were significantly higher in the BLI/INO group than in the control group (OS, 63.0 % vs. 31.2 %, p = 0.022; DFS 49.6 % vs. 22.9 %, p = 0.049), with comparable cumulative incidence of relapse (CIR, 41.3 % vs. 47.9 %; p = 0.767) and lower tendency of non-relapse mortality (NRM, 9.1 % vs. 29.2 %; p = 0.057). Multivariate analysis revealed that non-CR status before HCT was the only factor associated with poor OS (hazard ratio [HR], 4.263; p < 0.001) and higher CIR (HR, 2.250; p = 0.048). In patients in CR at HCT, there was no difference in HCT outcomes at 2 years (OS, 82.4 % vs. 58.8 %; p = 0.324; DFS, 64.2 % vs. 47.1 %; p = 0.496; CIR, 24.1 % vs. 41.2 %; p = 0.375; NRM, 11.8 % vs. 11.8 %; p = 0.950). BLI and/or INO therapy for RR-ALL was associated with better survival after HCT, probably due to the higher CR rate.
2025-01-03 | [Blinatumomab-based combination treatment for CD19-positive acute leukemia of an ambiguous lineage].
Acute leukemia of ambiguous lineage (ALAL) is a rare type of acute leukemia and is extremely difficult to treat. Here, we present six patients with CD19-positive ALAL who were successfully treated with blinatumomab-based combination treatment in the front-line setting. Five were diagnosed with B-cell/myeloid mixed phenotype acute leukemia (MPAL) and one with B-cell/T cell MPAL. All six patients achieved complete remission after one cycle of blinatumomab combination treatment. Furthermore, 3 (50%) patients achieved MRD-negative (<0.01%) by flow cytometry and 2 (50%) of four patients with evaluable molecular MRD achieved molecular remission. At some point during the treatment, 5 (83.3%) patients achieved MRD negativity and all four patients with evaluable molecular MRD had molecular remission. The overall survival was 100%, and the event-free survival was 83.3% after a median follow-up time of 15 months. This study provides preliminary evidence that blinatumomab-based combination therapy is an effective and safe treatment for patients with CD19-positive ALAL in the front-line setting.
2024-11-13 | Mixed-phenotype leukemia with TCF3::ZNF384 fusion presenting as an isolated mediastinal mass.
Acute leukemia with TCF3::ZNF384 is a distinct type of acute leukemia that present most commonly as B-acute lymphoblastic leukemia or mixed-phenotype acute leukemia (B/myeloid). We report the first case of TCF3::ZNF384 mixed-phenotype leukemia presenting as isolated extramedullary disease in the mediastinum. Diagnosis using RNA-sequencing and whole genome sequencing on the primary issue is illustrated.
2024-11-04 | [Update on acute leukemia of ambiguous lineage in 2023 - Recommendations of the French Society for Childhood and Adolescent Cancer and Leukemia (SFCE)].
Acute leukemias of ambiguous lineage (ALAL) represent between 3 and 5% of childhood AL. This term encompasses many subtypes of AL that have been defined according to the immunophenotypic profile based on the expression of various lineage markers. This classification has been modified and enriched during the last decade thanks to the improvement of molecular biology techniques, which have led to reconsider the ontogenic proximity existing between certain forms of ALAL. This increasing diagnostic complexity justifies the establishment of a close communication between clinicians and biologists in the management of these rare forms of AL. Indeed, the initial classification remains the cornerstone of their management since it conditions the future choice of therapeutic protocol. Thus, with the notable exception of undifferentiated forms of AL or AUL (for acute undetermined leukemia), it is now accepted that ALAL benefit from a lymphoid-based therapy approach. As with the management of "classic" acute lymphoblastic leukemias (ALL), the evaluation of response to treatment will determine the modalities of therapeutic intensification. The objective of improving the prognosis of ALAL justifies, in the long term, their future inclusion in the international ALLTogether protocol while continuing in-depth molecular exploration of these patients to identify targeted therapies.
2024-08-29 | KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives.
KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.
oligonucleotides
2026-03-19 | Aptamer-targeted hybrid nanoparticles based on human exosomes and LXR agonist-loaded liposomes for enhanced anti-AML therapy.
Despite advances in acute myeloid leukemia (AML) research, the treatment of AML is still inadequate, with relapse rates exceeding 50% in high-risk patients. There is an urgent need for the development of novel and synergistic therapies. In this study, we devised a Liver X Receptor (LXR) agonist, T0901317, employing the CD123 aptamer as a targeting element and exosome-liposome hybrid nanoparticles as delivery vehicles: aptamer mediated exosome-liposome hybridized nanoparticles@T0901317 (A-ELHN@T0901317). The A-ELHN@T0901317 was successfully synthesized with a uniform size of 162.0 ± 2.082 nm (PDI: 0.2368 ± 0.01845), ideal encapsulation efficiency (83.17 ± 2.881% for T0901317). In vitro, A-ELHN@T0901317 exhibited higher cellular uptake in CD123+ AML cells (molm-13) compared to non-targeted nanoparticles and a ∼50% reduction in cell proliferation relative to the control (p < 0.01). It induced G0/G1 cell cycle arrest and increased apoptosis via LXR-mediated cholesterol metabolism regulation (up-regulation of ARG1, ABCA1, ABCG1, LXRβ, FASN, ACACA, SREBF1, CDKN1A, and SCD genes). In vivo, A-ELHN@T0901317 group exhibited a substantially smaller fold increase in tumor fluorescence (21.38 ± 5.428-fold) than the control group (61.57 ± 17.73-fold, p < 0.0001), while significantly reduced damage to normal organs. Our findings suggest that A-ELHN@T0901317 represents a novel delivery method for the treatment of AML and highlights a promising direction for tumor-targeted therapy.
2025-09-08 | The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
Acute myeloid leukemia (AML) with rearrangement of the mixed lineage leukemia gene expresses MLL-AF9 fusion protein, a transcription factor that impairs differentiation and drives expansion of leukemic cells. In this work, the zinc finger protein "growth factor independent 1" together with the histone methyltransferase LSD1 is revealed to occupy the promoter and regulate the expression of the lncRNA ELDR (EGFR [epidermal growth factor receptor] long non-coding downstream RNA) in the rearranged Mixed Lineage Leukemia (MLL) (MLL-r) AML cell line THP-1. Forced ELDR overexpression enhanced the growth inhibition of an Lysine-Specific Demethylase 1 inhibitor (LSD1i)/all-trans retinoic acid (ATRA) combination treatment and reduced the capacity of these cells to generate leukemia in xenografts, leading to a longer leukemia-free survival. ELDR is found to bind the clamp protein Proliferating Cell Nuclear Antigen (PCNA) and the MCM5 helicases causing defects of DNA replication fork progression. Moreover, AML cells overexpressing ELDR had reduced chromatin accessibility and transcription at α-satellite repeats in centromeres. In addition, ELDR RNA was detected close to MLL-AF9 at centromeres suggesting that it impedes leukemic progression preferentially of MLL-r AML by interfering with both DNA replication and centromeric transcription. Our findings reveal novel functions of the lncRNA ELDR in DNA replication and centromere biology when expressed at high levels in AML cells with MLL rearrangements. These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be used as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.
2025-04-21 | Abstract 3252: Circulating tumor DNA (ctDNA) enables enhanced measurable residual disease (MRD) detection and non-invasive clonal profiling in acute myeloid leukemia (AML)
Abstract Introduction: Current MRD detection methods for AML (multiparameter flow cytometry and single-gene assays) are limited by suboptimal sensitivity, narrow coverage for molecular monitoring and clonal resolution, and/or reliance on invasive bone marrow biopsies. To address these issues, we developed AML-CAPP-Seq, a ctDNA-based assay leveraging a customized Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) approach to detect MRD and track clonal evolution. Methods: AML-CAPP-Seq integrates patient-specific hybrid capture panels (based on whole exome sequencing, WES) with a shared panel of 58 recurrently mutated ‘canonical’ AML genes to generate personalized MRD assays. We analyzed > 1000 biological samples from 56 AML patients (median follow-up: 19.5 months) and 21 healthy controls, comparing MRD detection in bone marrow mononuclear cells (BMMCs), peripheral blood mononuclear cells (PBMCs), and cell-free DNA from plasma (PB-ctDNA) and bone marrow (BM-ctDNA) against standard-of-care (SOC) MRD assays. Results: WES identified a median of 32.5 tumor single nucleotide variants (SNVs) per patient, allowing MRD detection in 100% of patients with a detection limit of <0.01% tumor fraction. Use of only canonical AML genes reduced coverage to 84%, while SOC single gene molecular MRD methods were applicable to just 32% of patients. Tumor burden in PB-ctDNA was highly correlated (r > 0.9) with other compartments and showed significantly higher tumor DNA levels at low disease burden states (median 3.8- and 2.9-fold enrichment compared to PBMCs and BMMCs respectively, p < 0.02), particularly in cases of extramedullary involvement. PB-ctDNA detected residual disease in 98.5% of samples with +MRD by SOC marrow-based methods and identified MRD in 47.4% of SOC-negative samples. Of these, 46.8% were from patients who later relapsed, while 50% ultimately reached MRD-negative status after further therapy. In CR1 patients (n = 48), PB-ctDNA identified MRD in 89.3% of those who relapsed, compared to 46.4% by SOC MRD and 35.7% by flow alone. PB-ctDNA MRD robustly predicted relapse-free survival (RFS, HR = 11.9, p = 7e-8) and overall survival (HR = 19.7, p = 5e-9), outperforming SOC methods (HR = 3.4, p = 5e-4 and HR = 5.2, p = 4e-6 respectively). For patients undergoing allogeneic SCT (n = 27), PB-ctDNA MRD clearance before and after SCT predicted RFS (p = 4e-4). Additionally, by monitoring dozens of tumor variants including indels and copy number alternations in a time-resolved fashion, AML-CAPP-Seq allowed detailed tracking of clonal dynamics over time. Conclusions: AML-CAPP-Seq offers ultrasensitive, noninvasive MRD detection in ctDNA superior to SOC methods without need for invasive BM evaluation. Personalized variant tracking ensures universal applicability across AML patients, enabling both MRD monitoring and clonal evolution profiling. Citation Format: Ruwan Gunaratne, Crystal Zhou, Sanjeeth Rajaram, Jesse W. Tai, Sky Kim, Kailee Tanaka, Charu Tiwari, Grace Gao, Mia Carleton, Brian J. Sworder, Gabriel N. Mannis, Michael S. Khodadoust, Ravindra Majeti, David Kurtz, Tian Yi Zhang. Circulating tumor DNA (ctDNA) enables enhanced measurable residual disease (MRD) detection and non-invasive clonal profiling in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3252.
2022-03-16 | Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia.
Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.This article is highlighted in the In This Issue feature, p. 2659.
2021-12-24 | miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia.
t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
other
2025-01-15 | Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
A mixed phenotype (MP) is a characteristic of de novo MP acute leukemia (MPAL), but it can also be found in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with MP and define acute myeloid leukemia with MP (AML-MP) and MPAL as 2 distinct groups by characterizing clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP has inferior responses (hazard ratio, 12.5; 95% confidence interval, 2.72-57.8; P = .001), whereas MPAL has better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52 [44%]) and TP53 (12/52 [23.1%]) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35 [23%]; P = .01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40 [2.5%] vs 10/28 [35.7%]; P = .0003). Last, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with MP.
2024-10-03 | [Molecular profiling of myeloid/natural killer (NK) cell precursor acute leukemia].
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.
2024-09-18 | Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia.
Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.
2024-08-30 | Genetic deletion of JAM-C in preleukemic cells rewires leukemic stem cell gene expression program in AML.
The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether "niche anchoring" of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of "not reached" after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656.
2024-05-21 | Clinicopathologic Features and Outcomes of Acute Leukemia Harboring Picalm::Mllt10 Fusion
The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutes and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutes' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.
cell therapies
2026-08-15 | TA-TMA occurring after sequential CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation: a case report.
Currently, CAR-T cell therapy bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a pivotal therapeutic strategy for refractory/relapsed hematologic malignancies. Sequential therapy with CD7 chimeric antigen receptor T (CAR-T) cells combined with allo-HSCT provides a novel therapeutic approach for T-lymphoid malignancies, CD7-highly expressed acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). This strategy circumvents the toxicities of conventional myeloablative conditioning chemotherapy and immunosuppressive agents, while achieving tumor eradication, hematopoietic reconstitution, and prevention of graft-versus-host disease (GVHD). Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare but life-threatening complication following allo-HSCT, associated with elevated non-relapse mortality (NRM). This article reports a case of early-onset TA-TMA in a patient with MPAL after CD7 CAR-T bridging to allo-HSCT. This study aims to enhance clinicians' awareness of the diagnosis and management of TA-TMA following CAR-T bridging to allo-HSCT, provide a reference for early identification and timely intervention, and further improve patient outcomes.
2026-04-16 | Durable deep molecular response via CD19 chimeric antigen receptor T-cell therapy combined with a third-generation tyrosine kinase inhibitor in acute leukemia of ambiguous lineage with the Philadelphia chromosome: a potential strategy for transplant-ineligible patients.
Not available.
2026-03-31 | Exploring mixed phenotype acute leukemia: Clinical, immunophenotypic, cytogenetic, and prognostic insights from a tertiary care center.
Mixed-phenotype acute leukemias (MPALs) are a rare and aggressive group of leukemias, accounting for approximately 2%-5% of all leukemia cases. MPAL is characterized by the expression of markers from more than one hematopoietic lineage, either myeloid and lymphoid, which can be identified through flow cytometry immunophenotyping. This study aims to describe the clinicopathological, immunophenotypic, and cytogenetic features of a cohort of 27 patients diagnosed with MPAL at our institution. We conducted a retrospective analysis of 27 consecutive MPAL cases diagnosed between January 2016 and September 2020 at our tertiary care center. All cases were classified based on the WHO 2016 diagnostic criteria using flow cytometry for immunophenotyping. Available cytogenetic and molecular data were also analyzed. Among 1622 acute leukemia cases diagnosed during the study period, 27 (1.7%) fulfilled the diagnostic criteria for MPAL. The cohort had a male-to-female ratio of 4.4:1, with a median age of 21 years. The cases were classified as B/myeloid (n = 16) and T/myeloid (n = 11). Cytogenetic data were available for 18 patients, of which 7 cases had a normal karyotype. The remaining cases displayed various abnormalities, including trisomy 8, t(8:14)(q11.2;q32), and t(9;22). The induction mortality rate was notably high at 54%, primarily due to infections and poor general condition of patients at presentation. No significant survival difference was observed between B/myeloid and T/myeloid subgroups. MPAL remains a rare and challenging leukemia to diagnose and treat, requiring precise immunophenotypic analysis for accurate classification. MPAL constituted a small proportion (1.7%) of acute leukemias in our cohort and was associated with extremely poor outcomes, reflected by the very high induction mortality (54%) and median survival of only 1 month. Survival did not differ significantly between B/myeloid and T/myeloid subtypes, underscoring the uniformly adverse prognosis. These findings highlight the urgent need for improved supportive care, early recognition, and integration of novel strategies-including timely allogeneic transplantation-to improve outcomes in this clinically challenging and prognostically adverse entity.
2026-03-28 | The Efficiency of Allotransplant in a Case of Acute Biphenotypic Myeloid and B-Lymphoid Leukemia (MPAL Myelo/B NOS) That Presented Concurrently with a Mediastinal Granulocytic Sarcoma Co-Expressing Lymphoid Markers Complicated by Cardiac Tamponade.
Background and Clinical Significance: Mixed-phenotype acute leukemia (MPAL) is a rare hematologic malignancy characterized by the co-expression of myeloid and lymphoid markers and is associated with poor prognosis. Myeloid sarcoma (MS), particularly in the mediastinum, is an uncommon extramedullary manifestation and is rarely reported in association with MPAL. Case Presentation: We report a rare case of mediastinal MS with biphenotypic features and pericardial extension occurring concurrently with MPAL, highlighting diagnostic challenges, therapeutic strategies, and long-term outcomes. We describe the clinical course, diagnostic workup, treatment, and follow-up of a 21-year-old woman who presented with cardiac tamponade secondary to a mediastinal mass. Histopathology and immunophenotyping established the diagnosis of mediastinal MS associated with MPAL (B/myeloid, NOS). Management included surgical cytoreduction, intensive induction chemotherapy, and consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) from an unrelated donor. Fertility preservation with oocyte retrieval, in vitro fertilization (IVF), and embryo cryopreservation was performed prior to conditioning. A focused literature review of MPAL cases with extramedullary involvement was conducted. The patient achieved complete remission following induction therapy and underwent allo-HSCT. Despite the historically poor prognosis of mediastinal MS and MPAL, she remains in sustained complete remission 13 years after diagnosis. A literature review identified only eight reported cases of MPAL with extramedullary disease, with mediastinal involvement described in a single case and allo-HSCT performed in only two patients. Conclusions: This case illustrates a rare presentation of MPAL with mediastinal myeloid sarcoma and cardiac tamponade, demonstrating that aggressive multimodal therapy including allo-HSCT may achieve durable remission even in high-risk presentations. Early multidisciplinary management and consideration of fertility preservation are essential in young patients.
2026-02-25 | Allogeneic Hematopoietic Stem Cell Transplantation for Children With Mixed Phenotype Acute Leukemia: A Single-Center Retrospective Study.
Mixed phenotype acute leukemia (MPAL) represents an uncommon but heterogenous disease, often posing both a diagnostic and therapeutic challenge. The purpose of this retrospective study was to analyze the overall survival, event-free survival, and severity of associated complications after allo-HSCT in children with MPAL, and provide feasible recommendations for the treatment of MPAL patients. We retrospectively analyzed a total of 14 pediatric patients with MPAL who received allo-HSCT at our center between January 2010 and June 2024. In terms of immunophenotype, coexpression of myeloid and B-lymphoid antigens was observed in 10 patients (71.4%), and myeloid and T-lymphoid antigens in 4 (28.6%). Chromosomal abnormalities were found in 8 patients (57.1%) and BCR/ABL(+) was the most common fusion gene (3/14; 21.4%). All 14 patients underwent allo-HSCT after achieving the CR1 (78.6% with MRD-negative status pretransplantation). Among the 14 transplanted children, the OS rate was 92.9% and the EFS rate was 85.7%. No significant difference in OS, EFS, and CIR rates between children with Haplo-HSCT and those with MSD-HSCT (P>0.05). The rate of acute GVHD was 57.1% (8/14), and the rate of chronic GVHD was 71.4%, of which 90% were assessed as mild cGVHD, with the skin being the most common organ involved in cGVHD. Only one patient developed TA-TMA and died from transplant-related complications. The children with MPAL who received allo-HSCT after MRD-negative CR often had a favorable disease control. Compared with patients receiving conventional chemotherapy, pediatric patients who received allo-HSCT showed a significant improvement in OS, EFS, and CIR rates. Although the incidence of cGVHD was relatively high, most of them were assessed as mild with no significant impact on daily activities.
small molecules
2026-09-01 | The Fanconi anemia pathway restrains MLL-rearranged leukemogenesis through suppressing non-homologous end joining-mediated genomic instability
Mixed lineage leukemia (MLL) rearrangements drive approximately 10% of acute leukemias, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Individuals with Fanconi anemia (FA), a hereditary DNA damage repair (DDR) disorder, are at markedly increased risk of AML, yet the interplay between FA deficiency and MLL-rearranged (MLL-r) leukemia remains unclear. Using murine models and human MLL-r leukemia cells, we show that the FA pathway suppresses leukemogenesis by limiting error-prone non-homologous end joining (NHEJ)-mediated genomic instability. Loss of FA components accelerates leukemia development, promotes leukemic stem cell expansion, and increases DNA damage through hyperactive NHEJ. Pharmacological NHEJ inhibition selectively impairs the survival of FA-deficient MLL-r leukemia cells, revealing a synthetic lethal vulnerability. Consistent with these findings, reduced FA pathway gene expression in patient samples correlates with poor prognosis and increased sensitivity to NHEJ inhibition. These findings identify NHEJ blockade as a promising targeted therapeutic strategy for high-risk MLL-r leukemia. Mutations in the Fanconi anemia (FA) DNA repair genes predispose to leukemia and bone marrow failure. Here, the authors discover that the FA pathway controls MLL-rearranged leukemia progression via blocking nonhomologous end joining-mediated genomic instability.
2026-08-28 | Venetoclax with azacitidine and dexamethasone: Non-cytotoxic induction therapy for T-cell leukemia and mixed-phenotype leukemia.
T-lineage acute leukemias are aggressive malignancies for which treatment options are limited. This study evaluated the efficacy and safety of a non-cytotoxic regimen combining venetoclax, azacitidine, and dexamethasone (VAD) as first-line induction therapy for T-cell acute lymphoblastic leukemia (T-ALL) and T/myeloid mixed-phenotype acute leukemia (T-Myeloid MPAL). We retrospectively analyzed the clinical parameters and survival data of 11 patients with newly-diagnosed T-ALL or T-Myeloid MPAL who received the VAD regimen. The complete remission (CR) rate and adverse events were assessed. Kaplan-Meier curves were constructed to evaluate survival outcomes. Among 11 patients (7 with early T-cell precursor [ETP] ALL, 2 with T-Myeloid MPAL, and 2 with non-ETP T-ALL), the overall CR rate after one cycle of VAD therapy was 90.9%, with 45.5% achieving measurable residual disease (MRD) negativity by flow cytometry. The historically poor-prognosis ETP-ALL subgroup showed an 85.7% CR rate (6/7), while both T-Myeloid MPAL cases attained MRD negativity. No tumor lysis syndrome or treatment-related mortality occurred. Over a median follow-up of 358 days, all 5 patients who received transplantations remained relapse-free. The VAD regimen demonstrated a high response rate and favorable safety, enabling effective transplantation bridging with avoidance of conventional cytotoxic therapy.
2026-06-26 | Mixed Phenotype Acute Leukemia: Lineage Assignment, Immunophenotypic Classification and Genetic Insights.
Mixed phenotype acute leukemia (MPAL) is a rare and biologically heterogeneous category characterized by discrete admixed populations of myeloid and lymphoid blasts (bilineal or mixed lineage) or with coexpression of lymphoid and myeloid markers in a single blast population (biphenotypic or mixed phenotype). Despite advances in diagnostic criteria, MPAL remains a significant diagnostic and therapeutic challenge due to its immunophenotypic complexity and genetic diversity. Accurate classification relies heavily on multiparameter flow cytometry immunophenotyping, integrated with cytogenetic and molecular studies. The current World Health Organization classification and International Consensus Classification recognize specific genetic subtypes, including MPAL with t(9;22)(q34.1;q11.2)/BCR::ABL1 and MPAL with KMT2A rearrangement, reflecting the increasing importance of genomic profiling in disease characterization. Recent genomic studies have revealed additional recurrent alterations involving transcription factors, epigenetic regulators, signaling pathways, and lineage-specifying genes, including ZNF384 rearrangements, BCL11B alterations, mutations involving PHF6, WT1, FLT3, and RUNX1, and mutations affecting chromatin remodeling and cytokine signaling pathways. Importantly, distinct genetic lesions appear to correlate with specific immunophenotypic patterns, suggesting biologically meaningful disease subsets and providing insights into mechanisms of lineage plasticity and leukemogenesis. This review summarizes the current understanding of the immunophenotypic and genetic landscape of MPAL, emphasizing the integration of morphologic, immunophenotypic, cytogenetic, and molecular findings into diagnosis and subclassification.
2026-06-12 | Effect of the Proteasome Inhibitor, Bortezomib, on Histone Modifications in Human Leukemic Cell Lines
Histone-modifying enzymes and histone post-translational modifications (PTMs) play key roles in the organization (euchromatin versus heterochromatin) and function (active versus silenced genes) of chromatin. The abundance and activity of these enzymes, along with their associated histone PTMs, are often altered in cancer cells, leading to deregulated gene expression. The expression of the KMT2A-MLLT3 protein, resulting from a chromosomal translocation in mixed-lineage leukemia (MLL), a subtype of acute myeloid leukemia, augments transcription elongation, promoting the expression of HOXA9 and MEIS1, genes that play critical roles in MLL development. Bortezomib, a proteasome inhibitor, has been effective in treating various cancers. In this study, we compared the impact of bortezomib on histone PTMs in the MLL cell line MOLM-13 and the chronic myeloid leukemic (CML) cell line K562. We report that MOLM-13 had a greater level of histone H2B monoubiquitinated at lysine 120 (H2BK120ub) and histone H3 dimethylated at lysine 79 (H3K79me2) (modifications involved in elongation) and similar levels of histone H2A monoubiquitinated at lysine 119 (H2AK119ub). Bortezomib treatment resulted in significant reductions in H2BK120ub and H2AK119ub levels, the loss of FAcilitates Chromatin Transcription (FACT) chromatin association in both cell lines, and the reduced transcript levels of genes involved in the development of MLL.
2026-06-06 | Genetic Landscape of Acute Leukemia of Ambiguous Lineage: A Single Cancer Center Experience.
Acute leukemias of ambiguous lineage (ALALs) are rare acute leukemias with poor prognosis, encompassing acute undifferentiated leukemia and mixed-phenotype acute leukemia. The fifth edition of the World Health Organization classification of hematolymphoid tumors recommends excluding ALAL cases with myelodysplasia-associated mutations and/or cytogenetic abnormalities from classification as acute undifferentiated leukemia or mixed-phenotype acute leukemia, instead categorizing them as acute myeloid leukemia with myelodysplasia (AML-MR; hereafter referred to as AML-MR/ALAL), a distinct entity with limited genetic and clinical characterization to date. In this study, the genetic and clinical characteristics of AML-MR/ALAL were investigated in comparison with those of ALAL and AML-MR. RUNX1 (7/11; 63.6%), WT1 (3/11; 27.3%), DNMT3A (2/11; 18.2%), TET2 (2/11; 18.2%), BCORL1 (2/11; 18.2%), and TP53 (2/11; 18.2%) were identified as the most frequently mutated genes in AML-MR/ALAL. Moreover, AML-MR/ALAL shared genetic features with AML-MR and was distinct from ALAL. Although no significant difference in overall survival was observed between AML-MR/ALAL and ALAL, patients with AML-MR/ALAL showed a trend toward worse prognosis. In summary, these findings suggest that AML-MR/ALAL may be more appropriately classified as AML-MR; however, validation in larger cohorts is required.
antibodies
2025-05-01 | Pre-transplant blinatumomab and/or inotuzumab ozogamicin therapy for relapsed/refractory acute lymphoblastic and B/myeloid mixed phenotype acute leukemia in adults.
Real-world data on blinatumomab (BLI) and inotuzumab ozogamicin (INO) for relapsed or refractory B-acute lymphoblastic leukemia (RR-ALL) before hematopoietic stem cell transplantation (HCT) are limited. To compare the efficacy of salvage therapy with BLI and/or INO and conventional chemotherapy as a bridge to HCT, we retrospectively evaluated patients with RR-ALL who underwent first HCT at our institute between 2004 and 2023. Based on whether they had received salvage therapy with BLI and/or INO, 70 recipients were divided into a BLI/INO (n = 22) and a control group (n = 48). The complete remission (CR) rate before HCT was higher in the BLI/INO group than in the control group (77.3 % vs. 35.4 %, p = 0.002). Two years after the first HCT, the overall survival (OS) and disease-free survival (DFS) were significantly higher in the BLI/INO group than in the control group (OS, 63.0 % vs. 31.2 %, p = 0.022; DFS 49.6 % vs. 22.9 %, p = 0.049), with comparable cumulative incidence of relapse (CIR, 41.3 % vs. 47.9 %; p = 0.767) and lower tendency of non-relapse mortality (NRM, 9.1 % vs. 29.2 %; p = 0.057). Multivariate analysis revealed that non-CR status before HCT was the only factor associated with poor OS (hazard ratio [HR], 4.263; p < 0.001) and higher CIR (HR, 2.250; p = 0.048). In patients in CR at HCT, there was no difference in HCT outcomes at 2 years (OS, 82.4 % vs. 58.8 %; p = 0.324; DFS, 64.2 % vs. 47.1 %; p = 0.496; CIR, 24.1 % vs. 41.2 %; p = 0.375; NRM, 11.8 % vs. 11.8 %; p = 0.950). BLI and/or INO therapy for RR-ALL was associated with better survival after HCT, probably due to the higher CR rate.
2025-01-03 | [Blinatumomab-based combination treatment for CD19-positive acute leukemia of an ambiguous lineage].
Acute leukemia of ambiguous lineage (ALAL) is a rare type of acute leukemia and is extremely difficult to treat. Here, we present six patients with CD19-positive ALAL who were successfully treated with blinatumomab-based combination treatment in the front-line setting. Five were diagnosed with B-cell/myeloid mixed phenotype acute leukemia (MPAL) and one with B-cell/T cell MPAL. All six patients achieved complete remission after one cycle of blinatumomab combination treatment. Furthermore, 3 (50%) patients achieved MRD-negative (<0.01%) by flow cytometry and 2 (50%) of four patients with evaluable molecular MRD achieved molecular remission. At some point during the treatment, 5 (83.3%) patients achieved MRD negativity and all four patients with evaluable molecular MRD had molecular remission. The overall survival was 100%, and the event-free survival was 83.3% after a median follow-up time of 15 months. This study provides preliminary evidence that blinatumomab-based combination therapy is an effective and safe treatment for patients with CD19-positive ALAL in the front-line setting.
2024-11-13 | Mixed-phenotype leukemia with TCF3::ZNF384 fusion presenting as an isolated mediastinal mass.
Acute leukemia with TCF3::ZNF384 is a distinct type of acute leukemia that present most commonly as B-acute lymphoblastic leukemia or mixed-phenotype acute leukemia (B/myeloid). We report the first case of TCF3::ZNF384 mixed-phenotype leukemia presenting as isolated extramedullary disease in the mediastinum. Diagnosis using RNA-sequencing and whole genome sequencing on the primary issue is illustrated.
2024-11-04 | [Update on acute leukemia of ambiguous lineage in 2023 - Recommendations of the French Society for Childhood and Adolescent Cancer and Leukemia (SFCE)].
Acute leukemias of ambiguous lineage (ALAL) represent between 3 and 5% of childhood AL. This term encompasses many subtypes of AL that have been defined according to the immunophenotypic profile based on the expression of various lineage markers. This classification has been modified and enriched during the last decade thanks to the improvement of molecular biology techniques, which have led to reconsider the ontogenic proximity existing between certain forms of ALAL. This increasing diagnostic complexity justifies the establishment of a close communication between clinicians and biologists in the management of these rare forms of AL. Indeed, the initial classification remains the cornerstone of their management since it conditions the future choice of therapeutic protocol. Thus, with the notable exception of undifferentiated forms of AL or AUL (for acute undetermined leukemia), it is now accepted that ALAL benefit from a lymphoid-based therapy approach. As with the management of "classic" acute lymphoblastic leukemias (ALL), the evaluation of response to treatment will determine the modalities of therapeutic intensification. The objective of improving the prognosis of ALAL justifies, in the long term, their future inclusion in the international ALLTogether protocol while continuing in-depth molecular exploration of these patients to identify targeted therapies.
2024-08-29 | KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives.
KMT2A (alias: mixed-lineage leukemia [MLL]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the KMT2A gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the KMT2A gene, their molecular impact, clinical aspects, and novel targeted therapies.
oligonucleotides
2026-03-19 | Aptamer-targeted hybrid nanoparticles based on human exosomes and LXR agonist-loaded liposomes for enhanced anti-AML therapy.
Despite advances in acute myeloid leukemia (AML) research, the treatment of AML is still inadequate, with relapse rates exceeding 50% in high-risk patients. There is an urgent need for the development of novel and synergistic therapies. In this study, we devised a Liver X Receptor (LXR) agonist, T0901317, employing the CD123 aptamer as a targeting element and exosome-liposome hybrid nanoparticles as delivery vehicles: aptamer mediated exosome-liposome hybridized nanoparticles@T0901317 (A-ELHN@T0901317). The A-ELHN@T0901317 was successfully synthesized with a uniform size of 162.0 ± 2.082 nm (PDI: 0.2368 ± 0.01845), ideal encapsulation efficiency (83.17 ± 2.881% for T0901317). In vitro, A-ELHN@T0901317 exhibited higher cellular uptake in CD123+ AML cells (molm-13) compared to non-targeted nanoparticles and a ∼50% reduction in cell proliferation relative to the control (p < 0.01). It induced G0/G1 cell cycle arrest and increased apoptosis via LXR-mediated cholesterol metabolism regulation (up-regulation of ARG1, ABCA1, ABCG1, LXRβ, FASN, ACACA, SREBF1, CDKN1A, and SCD genes). In vivo, A-ELHN@T0901317 group exhibited a substantially smaller fold increase in tumor fluorescence (21.38 ± 5.428-fold) than the control group (61.57 ± 17.73-fold, p < 0.0001), while significantly reduced damage to normal organs. Our findings suggest that A-ELHN@T0901317 represents a novel delivery method for the treatment of AML and highlights a promising direction for tumor-targeted therapy.
2025-09-08 | The lncRNA ELDR suppresses tumorigenicity of AML by interfering with DNA replication and chromatin accessibility.
Acute myeloid leukemia (AML) with rearrangement of the mixed lineage leukemia gene expresses MLL-AF9 fusion protein, a transcription factor that impairs differentiation and drives expansion of leukemic cells. In this work, the zinc finger protein "growth factor independent 1" together with the histone methyltransferase LSD1 is revealed to occupy the promoter and regulate the expression of the lncRNA ELDR (EGFR [epidermal growth factor receptor] long non-coding downstream RNA) in the rearranged Mixed Lineage Leukemia (MLL) (MLL-r) AML cell line THP-1. Forced ELDR overexpression enhanced the growth inhibition of an Lysine-Specific Demethylase 1 inhibitor (LSD1i)/all-trans retinoic acid (ATRA) combination treatment and reduced the capacity of these cells to generate leukemia in xenografts, leading to a longer leukemia-free survival. ELDR is found to bind the clamp protein Proliferating Cell Nuclear Antigen (PCNA) and the MCM5 helicases causing defects of DNA replication fork progression. Moreover, AML cells overexpressing ELDR had reduced chromatin accessibility and transcription at α-satellite repeats in centromeres. In addition, ELDR RNA was detected close to MLL-AF9 at centromeres suggesting that it impedes leukemic progression preferentially of MLL-r AML by interfering with both DNA replication and centromeric transcription. Our findings reveal novel functions of the lncRNA ELDR in DNA replication and centromere biology when expressed at high levels in AML cells with MLL rearrangements. These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be used as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.
2025-04-21 | Abstract 3252: Circulating tumor DNA (ctDNA) enables enhanced measurable residual disease (MRD) detection and non-invasive clonal profiling in acute myeloid leukemia (AML)
Abstract Introduction: Current MRD detection methods for AML (multiparameter flow cytometry and single-gene assays) are limited by suboptimal sensitivity, narrow coverage for molecular monitoring and clonal resolution, and/or reliance on invasive bone marrow biopsies. To address these issues, we developed AML-CAPP-Seq, a ctDNA-based assay leveraging a customized Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) approach to detect MRD and track clonal evolution. Methods: AML-CAPP-Seq integrates patient-specific hybrid capture panels (based on whole exome sequencing, WES) with a shared panel of 58 recurrently mutated ‘canonical’ AML genes to generate personalized MRD assays. We analyzed > 1000 biological samples from 56 AML patients (median follow-up: 19.5 months) and 21 healthy controls, comparing MRD detection in bone marrow mononuclear cells (BMMCs), peripheral blood mononuclear cells (PBMCs), and cell-free DNA from plasma (PB-ctDNA) and bone marrow (BM-ctDNA) against standard-of-care (SOC) MRD assays. Results: WES identified a median of 32.5 tumor single nucleotide variants (SNVs) per patient, allowing MRD detection in 100% of patients with a detection limit of <0.01% tumor fraction. Use of only canonical AML genes reduced coverage to 84%, while SOC single gene molecular MRD methods were applicable to just 32% of patients. Tumor burden in PB-ctDNA was highly correlated (r > 0.9) with other compartments and showed significantly higher tumor DNA levels at low disease burden states (median 3.8- and 2.9-fold enrichment compared to PBMCs and BMMCs respectively, p < 0.02), particularly in cases of extramedullary involvement. PB-ctDNA detected residual disease in 98.5% of samples with +MRD by SOC marrow-based methods and identified MRD in 47.4% of SOC-negative samples. Of these, 46.8% were from patients who later relapsed, while 50% ultimately reached MRD-negative status after further therapy. In CR1 patients (n = 48), PB-ctDNA identified MRD in 89.3% of those who relapsed, compared to 46.4% by SOC MRD and 35.7% by flow alone. PB-ctDNA MRD robustly predicted relapse-free survival (RFS, HR = 11.9, p = 7e-8) and overall survival (HR = 19.7, p = 5e-9), outperforming SOC methods (HR = 3.4, p = 5e-4 and HR = 5.2, p = 4e-6 respectively). For patients undergoing allogeneic SCT (n = 27), PB-ctDNA MRD clearance before and after SCT predicted RFS (p = 4e-4). Additionally, by monitoring dozens of tumor variants including indels and copy number alternations in a time-resolved fashion, AML-CAPP-Seq allowed detailed tracking of clonal dynamics over time. Conclusions: AML-CAPP-Seq offers ultrasensitive, noninvasive MRD detection in ctDNA superior to SOC methods without need for invasive BM evaluation. Personalized variant tracking ensures universal applicability across AML patients, enabling both MRD monitoring and clonal evolution profiling. Citation Format: Ruwan Gunaratne, Crystal Zhou, Sanjeeth Rajaram, Jesse W. Tai, Sky Kim, Kailee Tanaka, Charu Tiwari, Grace Gao, Mia Carleton, Brian J. Sworder, Gabriel N. Mannis, Michael S. Khodadoust, Ravindra Majeti, David Kurtz, Tian Yi Zhang. Circulating tumor DNA (ctDNA) enables enhanced measurable residual disease (MRD) detection and non-invasive clonal profiling in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3252.
2022-03-16 | Enhancer Hijacking Drives Oncogenic BCL11B Expression in Lineage-Ambiguous Stem Cell Leukemia.
Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.This article is highlighted in the In This Issue feature, p. 2659.
2021-12-24 | miR-130b and miR-128a are essential lineage-specific codrivers of t(4;11) MLL-AF4 acute leukemia.
t(4;11) MLL-AF4 acute leukemia is one of the most aggressive malignancies in the infant and pediatric population, yet we have little information on the molecular mechanisms responsible for disease progression. This impairs the development of therapeutic regimens that can address the aggressive phenotype and lineage plasticity of MLL-AF4-driven leukemogenesis. This study highlights novel mechanisms of disease development by focusing on 2 microRNAs (miRNAs) upregulated in leukemic blasts from primary patient samples: miR-130b and miR-128a. We show that miR-130b and miR-128a are downstream targets of MLL-AF4 and can individually drive the transition from a pre-leukemic stage to an acute leukemia in an entirely murine Mll-AF4 in vivo model. They are also required to maintain the disease phenotype. Interestingly, miR-130b overexpression led to a mixed/B-cell precursor (BCP)/myeloid leukemia, propagated by the lymphoid-primed multipotent progenitor (LMPP) population, whereas miR-128a overexpression resulted in a pro-B acute lymphoblastic leukemia (ALL), maintained by a highly expanded Il7r+c-Kit+ blast population. Molecular and phenotypic changes induced by these two miRNAs fully recapitulate the human disease, including central nervous system infiltration and activation of an MLL-AF4 expression signature. Furthermore, we identified 2 downstream targets of these miRNAs, NR2F6 and SGMS1, which in extensive validation studies are confirmed as novel tumor suppressors of MLL-AF4+ leukemia. Our integrative approach thus provides a platform for the identification of essential co-drivers of MLL-rearranged leukemias, in which the preleukemia to leukemia transition and lineage plasticity can be dissected and new therapeutic approaches can be tested.
other
2025-01-15 | Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype.
A mixed phenotype (MP) is a characteristic of de novo MP acute leukemia (MPAL), but it can also be found in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with MP and define acute myeloid leukemia with MP (AML-MP) and MPAL as 2 distinct groups by characterizing clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP has inferior responses (hazard ratio, 12.5; 95% confidence interval, 2.72-57.8; P = .001), whereas MPAL has better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52 [44%]) and TP53 (12/52 [23.1%]) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35 [23%]; P = .01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40 [2.5%] vs 10/28 [35.7%]; P = .0003). Last, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with MP.
2024-10-03 | [Molecular profiling of myeloid/natural killer (NK) cell precursor acute leukemia].
Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.
2024-09-18 | Multiomic single cell sequencing identifies stemlike nature of mixed phenotype acute leukemia.
Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.
2024-08-30 | Genetic deletion of JAM-C in preleukemic cells rewires leukemic stem cell gene expression program in AML.
The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether "niche anchoring" of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of "not reached" after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656.
2024-05-21 | Clinicopathologic Features and Outcomes of Acute Leukemia Harboring Picalm::Mllt10 Fusion
The PICALM::MLLT10 fusion is a rare but recurrent cytogenetic abnormality in acute leukemia, with limited clinicopathologic and outcome data available. Herein, we analyzed 156 acute leukemia patients with PICALM::MLLT10 fusion, including 12 patients from our institutes and 144 patients from the literature. The PICALM::MLLT10 fusion preferentially manifested in pediatric and young adult patients, with a median age of 24 years. T-lymphoblastic leukemia/lymphoma (T-ALL) constituted 65% of cases, acute myeloid leukemia (AML) 27%, and acute leukemia of ambiguous lineage (ALAL) 8%. About half of T-ALL were classified as an early T-precursor (ETP)-ALL. In our institutes' cohort, mediastinum was the most common extramedullary site of involvement. Eight of 12 patients were diagnosed with T-ALL exhibiting a pro-/pre-T stage phenotype (CD4/CD8-double negative, CD7-positive), and frequent CD79a expression. NGS revealed pathogenic mutations in 5 of 6 tested cases, including NOTCH1, and genes in RAS and JAK-STAT pathways and epigenetic modifiers. Of 138 cases with follow-up, pediatric patients (<18 years) had 5-year overall survival (OS) of 71%, significantly better than adults at 33%. The 5-year OS for AML patients was 25%, notably shorter than T-ALL patients at 54%; this distinction was observed in both pediatric and adult populations. Furthermore, adult but not pediatric ETP-ALL patients demonstrated inferior survival compared to non-ETP-ALL patients. Neither karyotype complexity nor transplant status had a discernible impact on OS. In conclusion, PICALM::MLLT10 fusion is most commonly seen in T-ALL patients, particularly those with an ETP phenotype. AML and adult ETP-ALL patients had adverse prognosis. PICALM::MLTT10 fusion testing should be considered in T-ALL, AML, and ALAL patients.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Acute leukemia of ambiguous lineage, including 1 approved therapy.
1 orphan drug designation for Acute leukemia of ambiguous lineage, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
revumenib [Revuforj] | small molecules | FDA | Approved | Syndax Pharmaceuticals, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.