RARE DISEASE
Juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia
Synonyms: JMML, Juvenile chronic myelomonocytic leukemia
Synonyms: JMML, Juvenile chronic myelomonocytic leukemia
Synonyms: JMML, Juvenile chronic myelomonocytic leukemia
Drug discovery
2
drugs
With orphan designations
Overview
Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric myelodysplastic/myeloproliferative neoplasm driven by RAS pathway mutations (PTPN11, KRAS, NRAS, CBL, or NF1). It primarily affects children <4 years, characterized by monocytosis, organomegaly, and hematopoietic failure. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option, achieving 50-73% 5-year survival, though relapse occurs in 24-40% of cases [1][4][8][17]. Prognostic factors include age <2 years, platelet count >33×10⁹/L, and low fetal hemoglobin levels [1][4].
Therapies
HSCT: Myeloablative conditioning (busulfan-based regimens) achieves 66-74% 5-year survival [4][8][17]
Hypomethylating agents: Azacitidine (FDA-approved) induces partial remissions in 61-88% pre-HSCT [1][12][17]
Relapse management: Second HSCT salvages 33% of relapsed patients; decitabine maintenance reduces relapse risk to 8% [3][17][4]
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
487 drug discovery papers about Juvenile myelomonocytic leukemia, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
487 drug discovery papers about Juvenile myelomonocytic leukemia, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-08 | Bilateral testicular infiltration as the initial presentation of NRAS-mutant juvenile myelomonocytic leukemia: rapid molecular remission following azacitidine and haploidentical stem cell transplantation.
Juvenile myelomonocytic leukemia (JMML) rarely manifests with extramedullary involvement beyond spleen, liver, or skin; testicular infiltration at diagnosis is unreported. We describe a Novel Case of bilateral testicular leukemic infiltration as the initial presentation of NRAS-mutant JMML in a toddler, with rapid remission following azacitidine bridging and haploidentical HSCT. A 2-year-old boy presented with pallor, abdominal distension, and bilateral scrotal swelling. Labs: leukocytosis (58 × 10⁹/L, monocytes 12.8 × 10⁹/L), anemia (Hb 8.2 g/dL), HbF 22%. BM confirmed JMML with NRAS p.G12D (VAF 42%). No pathogenic variants were detected in KRAS, PTPN11, CBL, or NF1. Conventional cytogenetic analysis demonstrated a normal male karyotype (46,XY). US: testes enlarged (18.8/18.2 mL) with hypoechoic infiltration. Azacitidine (75 mg/m²/d × 5, 2 cycles) reduced counts and size. Paternal haplo-HSCT (Flu-Treo-TT conditioning, PTCy) engrafted D + 18; testes normal at 6 weeks, molecular remission (NRAS-) at 3 months. This novel case underscores the efficacy of azacitidine and haploidentical HSCT for NRAS-mutant JMML with testicular involvement. Routine genital examination and ultrasound are recommended for male patients.
2026-06-04 | Successful Sirolimus Therapy in Steroid-Refractory RAS-Associated Autoimmune Lymphoproliferative Disorder with Mosaic KRAS Mutation
Introduction Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective lymphocyte apoptosis caused by abnormalities in the FAS signaling pathway and presents with lymphadenopathy, splenomegaly, and autoimmune manifestations. RAS-associated autoimmune lymphoproliferative disorder (RALD) is classified as an ALPS-related disorder and is caused by somatic mutations in NRAS or KRAS, resulting in constitutive activation of the RAS signaling pathway. This leads to impaired apoptosis, abnormal lymphocyte proliferation, and autoimmune manifestations. Compared with classic ALPS, RALD may exhibit distinct clinical features such as mild monocytosis or juvenile myelomonocytic leukemia (JMML)-like findings, making accurate differential diagnosis essential. Although glucocorticoids are generally considered first-line therapy, optimal management strategies for glucocorticoid-refractory cases remain to be established. Case Presentation A two-year-old boy who had been diagnosed with autoimmune hemolytic anemia at eight months of age developed transient thrombocytopenia and nephrotic syndrome. His cytopenia was unresponsive to glucocorticoid therapy, and he became transfusion dependent. Genetic testing later identified a mosaic KRAS variant (p.Gly13Asp), leading to the diagnosis of RALD. Based on recent reports suggesting the possibility of efficacy for mTOR inhibitors in monogenic disorders characterized by immune dysregulation and lymphoproliferation, an investigator-initiated clinical trial using sirolimus was proposed and initiated after obtaining consent. After the introduction of sirolimus, the patient achieved transfusion independence. However, his clinical course was complicated by secondary hypogammaglobulinemia, which currently requires ongoing immunoglobulin replacement therapy. Discussion Sirolimus suppresses the activation and proliferation of T and B lymphocytes, thereby controlling pathological lymphoproliferation and autoimmune manifestations in RALD. This case highlights the clinical utility of sirolimus as a promising therapeutic option for glucocorticoid-refractory RALD.
2026-06-03 | Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia.
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myelodysplastic syndrome or myeloproliferative disorder for which hematopoietic stem cell transplantation remains the only curative option; however, outcomes are particularly poor in patients harboring PTPN11 (encodes SHP2 phosphatase) mutations. Using a Shp2E76K/+ JMML mouse model, we identify a pathogenic IL-17A/PTGS2/NLRP3 signaling axis that drives bone marrow inflammation, suppresses antitumor immunity, and promotes leukemic progression. Shp2E76K/+ mice exhibited profound immune dysregulation, characterized by expansion of regulatory T cells (Tregs), increased T-cell exhaustion, and impaired cytotoxic function with reduced CD4⁺ and CD8⁺ T-cell frequencies. Mechanistically, mutant macrophages upregulated IL-17A, triggering NLRP3 inflammasome activation, PTGS2 induction, caspase-1 cleavage, and IL-1β maturation, thereby amplifying inflammatory signaling within the marrow niche. Therapeutically, IL-17A neutralization suppressed inflammasome activity, while combined inhibition of NLRP3 and PTGS2 restored cytotoxic T-cell function, reduced systemic and marrow inflammation, reversed myeloproliferation, and significantly prolonged survival in Shp2E76K/+ mice. Importantly, ex vivo treatment of primary JMML patient samples with dual NLRP3/PTGS2 inhibition combined with MEK blockade significantly reduced leukemic progenitor colony formation, supporting translational relevance. In patient-derived xenograft models of PTPN11-mutant JMML, dual NLRP3/PTGS2 inhibition combined with MEK blockade most effectively reduced leukemic burden, decreased human CD45⁺ engraftment, and depleted leukemic CD34⁺CD38⁺ progenitors and GMPs while restoring MEP populations, resulting in significantly improved overall survival. Together, these findings establish IL-17A/PTGS2/NLRP3 signaling as a central driver of immune suppression and myeloid expansion in PTPN11-mutant JMML and highlight combinatorial anti-inflammatory targeting as a promising therapeutic strategy for this high-risk disease.
2026-05-27 | Molecular Advances in Juvenile Myelomonocytic Leukemia and Associated RASopathy.
Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes-PTPN11, NRAS, KRAS, NF1, or CBL-establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention.
2026-05-06 | The role of RAS mutations in leukemia progression, differentiation, and drug resistance.
Mutations in the RAS gene family (NRAS, KRAS) are critical drivers of late-stage acute myeloid leukemia (AML) progression. They are frequently detected in relapsed/refractory AML and AML transformed from myelodysplastic syndrome (MDS). Occurring as late-stage genetic events, RAS mutations synergize with early drivers to promote leukemogenesis. While mutually exclusive with FLT3-ITD mutations, they coexist with KIT, RUNX1, CEBPA mutations and MLL rearrangements. Granulocyte-monocyte progenitors (GMPs) serve as the cellular origin for RAS-mutant leukemia stem cells (LSCs). Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.
cell therapies
2025-11-05 | HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR CHILDREN WITH JUVENILE MYELOMONOCYTIC LEUKEMIA
transplant.One NRAS-mutated patient only received 6 courses of azacitidine and had resolution of disease without HSCT.Overall survival in 10 patients, with a median FU time of 3yr9mo since diagnosis and 3yr3mo after first HSCT (n=9) is 90%.(Two patients are within 1 year from first or second HSCT and one is prior to first HSCT and thus outcome cannot yet be reported).Conclusions: Overall survival in the Dutch cohort is excellent.Three of four patients with relapse after first transplant and more than 1yr after a second (or third) transplant are disease free.
2025-11-03 | Clinical outcome of hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia: A Single center in China
Abstract Objective: To evaluate the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in the treatment of juvenile myelomonocytic leukemia (JMML). Methods: A retrospective analysis was conducted on 142 JMML pediatric patients who underwent HSCT at our center from October 2018 to February 2025. The median age at transplantation was 33 months (range: 11–99 months). The transplantation methods comprised: haploidentical + cord blood complementary transplantation (CT) (83 cases), haploidentical donor lymphocyte infusion (DLI) + cord blood transplantation (DLI+CB) (19 cases), unrelated donor transplantation (MUD) (27 cases), haploidentical post-transplant cyclophosphamide (PTCy) transplantation (PBSCT) (9 cases), and haploidentical ex vivo T-cell-depleted (TDH) transplantation (4 cases). In the CT group, haploidentical peripheral blood stem cells (PBSCs) (MNC >15×10^8/kg) were infused on day 0. GVHD prophylaxis included cyclophosphamide on days +3 and +4, along with FK506 and mycophenolate mofetil (MMF). Unrelated cord blood was infused on day +6. For the DLI + CB group, haploidentical donor lymphocytes (4–8×10^8/kg) were administered on day -11, followed by conditioning with CY, BU, TT, and Flu from day -8 to -3. Unrelated cord blood was infused on day 0, the unrelated cord blood matching requires ≥7/10 HLA locus , and Kir assay was carried out at the same time. Cord blood with Haplotype Cen-Bx was preferred. GVHD prophylaxis included FK506 and MMF. Among the 27 unrelated donor transplantations, 25 were 10/10 HLA-matched, and 2 were 9/10 matched. The conditioning regimen consisted of BU+CY+TT+Flu±ATG-F, with a median PBSC mononuclear cell count of 8.6×10^8/kg infused on day 0. GVHD prophylaxis included FK506 and MMF. The haploidentical PTCy group followed the same infusion strategy as the complementary group. Four patients received ex vivo αβT-cell-depleted (TDH) transplantation without routine post-transplant immunosuppression. Results: With a median follow-up of 45 months (range: 7–81 months). The overall survival (OS) and leukemia-free survival (LFS) rates for all 142 patients were 92% and 91.7%, respectively. All 4 TDH transplant patients survived. The OS rates were 97.5% for the CT group (83 cases), 82.3% for the DLI + CB group (19 cases), 86.7% for the MUD group (27 cases), and 77.8% for the haploidentical PTCy group (9 cases). No statistically significant differences were observed between groups (P=0.057). The cumulative incidence of grade II–IV acute GVHD was 16.2% (23 cases), including 7 cases of grade III–IV. Chronic GVHD occurred in 18.3% (26 cases), primarily involving the skin, with 2 cases affecting the lungs, 1 the joints, and 2 the liver. Post-transplant viral reactivation was mostly transient, with HHV6 being the most common. Two cases progressed to viral encephalitis. Other viral reactivations included 5 cases of CMV and 2 of adenovirus. Three cases of veno-occlusive disease (VOD) were reported, 2 of which were mild. Conclusion: HSCT demonstrates significant clinical efficacy and relative safety in treating JMML. Different transplantation methods yielded high survival rates, with complementary transplantation showing particular advantages. TDH transplantation exhibited promising preliminary results, warranting further exploration.
2025-08-04 | Tandem CD19/CD22 CAR T-cells as potential therapy for children and young adults with high-risk r/r B-ALL.
Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches. We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL. Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%-100%). Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01). This work was supported by a grant from the Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects "Advanced Cell Therapy Unit Hospital Universitario La Paz" and JM "Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia" and "Terapia avanzada CAR-T CD19/CD22", Ayuda Nominativa de la Consejería de Investigación, Comunidad de Madrid, Spain. Work in MI lab was funded by a grant from the Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.
2025-06-04 | [Genetic and clinical characteristics of children with RAS-mutated juvenile myelomonocytic leukemia].
To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
2025-05-09 | Successful Haplo-hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child with Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case
Background: Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by bilateral radial aplasia with preserved thumbs and early-onset thrombocytopenia. While hematologic and skeletal abnormalities are hallmarks of the condition, its association with hematologic malignancies is exceedingly rare, with only a few reported cases of leukemia. Juvenile myelomonocytic leukemia (JMML) is an uncommon pediatric myelodysplastic/myeloproliferative neoplasm frequently linked to RAS pathway mutations. The co-occurrence of JMML in a patient with TAR syndrome has not been previously documented. Case Presentation: We report the case of a male infant diagnosed with TAR syndrome based on clinical features and molecular confirmation of a homozygous RBM8A c.-21G>A mutation. The patient presented initially with persistent thrombocytopenia, skeletal deformities, and neonatal sepsis-like symptoms. At two years of age, he developed pancytopenia and progressive splenomegaly. Bone marrow examination and molecular studies confirmed JMML with a pathogenic NF1 mutation. He underwent successful haploidentical hematopoietic stem cell transplantation (HSCT) from a sibling donor, following a conditioning regimen of melphalan, treosulfan, cyclophosphamide, and anti-thymocyte globulin. The patient achieved full donor chimerism and hematologic remission with stable engraftment. Conclusion: This case represents, to our knowledge, one of the very few—if not the first—reported instances of successful HSCT for JMML in a patient with TAR syndrome. It underscores the importance of vigilant surveillance in TAR patients for potential malignant transformation and demonstrates the curative potential of HSCT in complex congenital and hematologic overlap syndromes.
antibodies
2026-03-04 | Data from Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia
<div>Abstract<p>Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible <i>Ptpn11</i><sup><i>E76K</i></sup> mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.</p>Significance:<p>Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic <i>PTPN11</i> mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities.</p><p><a href="https://aacrjournals.org/bloodcancerdiscov/article-abstract/doi/10.1158/2643-3230.BCD-26-0006" target="_blank"><i>See related commentary by Miao and Xu, pp. 168</i></a></p></div>
2026-02-17 | Prevention of relapse of juvenile myelomonocytic leukemia (JMML) by inhibition of immune checkpoint CD47
Juvenile myelomonocytic leukemia (JMML) is an aggressive childhood myeloid malignancy driven by RAS pathway mutations, marked by clonal expansion and tissue infiltration of myeloid cells, including macrophages. This study investigated the role of macrophage polarization, phagocytic function, and CD47-mediated immune evasion in JMML pathogenesis. Analysis of human PTPN11-mutated JMML spleen samples revealed an enrichment of pro-inflammatory M1-like macrophages compared to KRAS-mutated cases and controls. Both human JMML macrophages and murine Ptpn11-mutant macrophages retained phagocytic capacity, with M1-like subsets exhibiting the highest activity. CD47, an immune checkpoint ligand that inhibits phagocytosis, was overexpressed in JMML cells, and its blockade enhanced macrophage-mediated clearance in vitro. In a patient-derived xenograft model, CD47 inhibition with magrolimab reduced splenic leukemia burden but showed limited efficacy in the bone marrow, with no synergistic effect observed when combined with azacitidine. These findings demonstrate that JMML macrophages remain functionally active and contribute to disease-associated inflammation, while CD47 blockade offers partial therapeutic benefit. Our study underscores the complex interplay between macrophage polarization, immune evasion, and inflammatory signaling in JMML, providing insights for future targeted therapies.
2025-12-22 | Juvenile myelomonocytic leukemia stem cells are sensitive to NK cell-mediated lysis and express targetable antigens.
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm for which hematopoietic stem cell transplantation is the only curative treatment. Innovative therapies are needed to address high rates of morbidity, treatment-related mortality, and relapse. Monoclonal antibodies and adoptive cell transfer of natural killer (NK) cells or T cells are approved or being investigated for other myeloid leukemias; however, their activity against JMML warrants further investigation. In this study, we hypothesized that NK cells may effectively target JMML tumor cells. Mass cytometry was used to evaluate the expression of NK cell-activating and -inhibitory ligands and candidate target antigens on the monocytic and stem cell subsets of JMML. Monocytes from healthy donors and monocytic subsets of JMML were similar in NK cell ligand expression, and JMML monocytes were resistant to NK cell cytotoxicity in vitro. However, NK cells effectively controlled proliferation of JMML colony-forming cells. CD34+CD38- JMML stem cells express a broad repertoire of NK cell ligands similar to that of acute myeloid leukemia stem cells; and CD33, CD44, and CD47 were expressed by both CD34+CD38- stem cells and CD34+CD38+ progenitors in JMML. This suggests that JMML may be responsive to NK cell-mediated activity, and that targeting CD33, CD44, or CD47 may facilitate eradication of JMML.
2025-12-05 | Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML. Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic PTPN11 mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities. See related commentary by Miao and Xu, pp. 168.
2025-11-07 | Novel humanized loss-of-function NF1 mouse model of juvenile myelomonocytic leukemia.
Juvenile myelomonocytic leukemia (JMML) is a fatal pediatric cancer characterized by classical features such as splenomegaly, monocytosis, and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity, with RAS pathway mutations being the major drivers. Mutations causing loss-of-function of the Neurofibromin 1 gene (NF1LOF) occur in ∼20% of patients with JMML. NF1LOF drives upregulation of RAS/MAPK/PI3K pathways that leads to aggressive proliferation/differentiation of immature myeloid cells. Hematopoietic stem cell transplantation is the only curative option, but relapse occurs in ∼50% of patients, indicating an urgent need for novel and targeted therapeutic strategies. However, low patient sample availability and a lack of reliable disease models have made it difficult to study and treat JMML. Using CRISPR/Cas9, we have generated NF1LOF in human umbilical cord blood-derived hematopoietic stem and progenitor cells (HSPCs). We achieved a high gene knockout rate of ∼89% and concomitant loss of NF1 protein in the modified HSPCs. Importantly, NF1LOF cells displayed marked GM-CSF hypersensitivity in in vitro colony-forming unit assays, mirroring JMML. When transplanted into NSG-SGM3 mice, they caused rapid lethality (median survival of 32 days), myeloid expansion, tissue infiltration (spleen, liver, and lungs), and specific upregulation of RAS/MAPK pathway and STAT5 genes, consistent with patient profiles. This first humanized NF1LOF mouse model recapitulates key JMML features, enabling investigation of disease mechanisms and targeted therapies.
oligonucleotides
2023-06-14 | RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia
RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS-mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.
2021-03-11 | Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective
Increasing evidence indicates an association between the incidence of Alzheimer's disease (AD) and cancer development. Despite advances being made by comparisons from epidemiological studies, common pathways and molecular mechanisms, little is known about the identities of the circular RNAs (circRNAs) involved in the development and progression of these two pathologies and their possible correlations. The aim of this study was to explore the circRNA relationship between AD and cancer.In this investigation, circRNAs that were significantly dysregulated in AD or associated with AD diagnosis, clinical dementia severity, and neuropathological severity, were examined in a large panel of 28 cancer types. On the basis of shared abnormal circRNAs in AD and cancers, we constructed a circRNA-micro RNA (miRNA)-messenger RNA (mRNA) network by leveraging experimentally identified miRNA-circRNA and miRNA-mRNA interactions from crosslinking-immunoprecipitation sequencing data.An inverse correlation of expression pattern was found in acute myeloid leukemia, juvenile myelomonocytic leukemia, renal cell carcinoma, and myelofibrosis. CircRNAs associated with AD diagnosis and clinical severity demonstrated negative correlation in more cancer types. Notably, differentially expressed candidate circRNAs in temporal lobe epilepsy were not associated with any cancers. Gene Ontology and KEGG pathway analysis suggested the circRNA-regulated genes are significantly associated with interleukin-12-mediated signaling and viral response. CircPICALM, circRTN4 and circMAN2A1 are the hub nodes in the circRNA-miRNA-target network.Our results indicated the relevance of inflammation signaling as a common pathogenesis shared by cancer and AD and provided novel insight for therapeutics targeting circRNAs.
2021-01-04 | Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid
Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.
2020-12-30 | Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia
Mutations in the CBL gene were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
2019-01-30 | Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm.
Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the Sipa1-/- MPN mouse model, we find that Sipa1 deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered Sipa1-/- BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated Dicer1, Kitl, Angptl1, Cxcl12, and Thpo in the Sipa1-/- BM cellular niches. Our data suggest that Sipa1 expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, Sipa1 loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring Sipa1 expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN.
other
2025-02-20 | Noonan Syndrome, Cancer Risk, and Growth Hormone Treatment.
Cancer can occur in patients with Noonan syndrome (NS). Review of English literature revealed that myeloproliferative diseases are the most prevalent, followed by intracranial tumours. There is no genotype phenotype relationship between germline pathogenic variants so it not possible to precisely predict cancer risk in NS, however some PTPN11 variants are exclusively detected in juvenile myelomonocytic leukemia and are not observed in other types of cancer. Among patients on growth hormone, cancer development was reported in seven patients with genetically confirmed NS, and five patients with clinically diagnosed NS. However, information on growth hormone dose, timing, and follow-up characteristics in these cases is heterogeneous. In the light of current data, especially in cases for whom growth hormone therapy is considered, the diagnosis should be genetically confirmed, and the results of genetic analysis should be compared with the cases reported in the literature. Families should be informed about possible cancer risk and in cases predisposing to juvenile myelomonocytic leukemia, early initiation of growth hormone therapy should be avoided.
2024-09-18 | Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.
Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n = 58) than in the pre-DF era (31% vs. 13%, p = .04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p = .04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p < .01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p = .01) and juvenile myelomonocytic leukemia (OR = 8.98, p = .04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.
2022-08-02 | Overexpression, biochemical characterization, and anticancer activates of L-asparaginase from Bacillus subtilis
L-asparaginases convert L-asparagine into L-aspartate and ammonia. The L-asparaginase from Bacillus subtilis was cloned and expressed in the E. coli strain BL21(DE3)pLysS in the current study. Using glutathione sepharose 4B column chromatography, the L-asparaginase enzyme was uniformly purified 173.34 times, with a final specific activity of 1769.13 IU/mg protein and a yield of 56.14%. The isolated enzyme was identified as a 36 kDa polypeptide chain by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The immobilized enzyme was placed on top of the Ca alginate beads. The immobilized enzyme is quite stable and retains the majority of its activity at 4 °C (74 percent). The enzymatic and structural characteristics of free and immobilized recombinant L-asparaginase were studied. The activity of the free enzyme peaked after 30 min of incubation at pH 8.0 and 45 °C. After 30 minutes at 50 °C, the immobilized enzyme showed its peak activity at a pH of 8.5. The refined enzyme's amino acid makeup was identified. An enzyme that heals leukemia, Bacillus subtilis L-asparaginase, can be successfully mass-produced using this technique.
2019-02-01 | Targeting cell-bound MUC1 on myelomonocytic, monocytic leukemias and phenotypically defined leukemic stem cells with anti-SEA module antibodies
Cell surface molecules aberrantly expressed or overexpressed by myeloid leukemic cells represent potential disease-specific therapeutic targets for antibodies. MUC1 is a polymorphic glycoprotein, the cleavage of which yields two unequal chains: a large extracellular α subunit containing a tandem repeat array bound in a strong noncovalent interaction to a smaller β subunit containing the transmembrane and cytoplasmic domains. Because the α-chain can be released from the cell-bound domains of MUC1, agents directed against the α-chain will not effectively target MUC1+ cells. The MUC1 SEA (a highly conserved protein module so called from its initial identification in a sea urchin sperm protein, in enterokinase, and in agrin) domain formed by the binding of the α and β chains represents a stable structure fixed to the cell surface at all times. DMB-5F3, a partially humanized murine anti-MUC1 SEA domain monoclonal antibody, was used to examine MUC1 expression in acute myeloid leukemia (AML) and was found to bind acute myelomonocytic and monocytic leukemia (AML-M4 and AML-M5) cell lines. We also examined monocytic neoplasms freshly obtained from patients including chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, which were found to uniformly express MUC1. CD34+/lin-/CD38- or CD38+ presumed leukemic stem cell populations from CD34+ AML and CD34-CD38- or CD38+ populations from CD34- AML were also found to express MUC1, although at low percentages. Based on these studies, we generated an anti-MUC1 immunotoxin to directly gauge the cytotoxic efficacy of targeting AML-bound MUC1. Using single-chain DMB-5F3 fused to recombinant gelonin toxin, the degree of AML cytotoxicity was found to correlate with MUC1 expression. Our data support the use of an anti-MUC1 SEA module-drug conjugates to selectively target and inhibit MUC1-expressing myelomonocytic leukemic cells.
small molecules
2026-08-08 | Bilateral testicular infiltration as the initial presentation of NRAS-mutant juvenile myelomonocytic leukemia: rapid molecular remission following azacitidine and haploidentical stem cell transplantation.
Juvenile myelomonocytic leukemia (JMML) rarely manifests with extramedullary involvement beyond spleen, liver, or skin; testicular infiltration at diagnosis is unreported. We describe a Novel Case of bilateral testicular leukemic infiltration as the initial presentation of NRAS-mutant JMML in a toddler, with rapid remission following azacitidine bridging and haploidentical HSCT. A 2-year-old boy presented with pallor, abdominal distension, and bilateral scrotal swelling. Labs: leukocytosis (58 × 10⁹/L, monocytes 12.8 × 10⁹/L), anemia (Hb 8.2 g/dL), HbF 22%. BM confirmed JMML with NRAS p.G12D (VAF 42%). No pathogenic variants were detected in KRAS, PTPN11, CBL, or NF1. Conventional cytogenetic analysis demonstrated a normal male karyotype (46,XY). US: testes enlarged (18.8/18.2 mL) with hypoechoic infiltration. Azacitidine (75 mg/m²/d × 5, 2 cycles) reduced counts and size. Paternal haplo-HSCT (Flu-Treo-TT conditioning, PTCy) engrafted D + 18; testes normal at 6 weeks, molecular remission (NRAS-) at 3 months. This novel case underscores the efficacy of azacitidine and haploidentical HSCT for NRAS-mutant JMML with testicular involvement. Routine genital examination and ultrasound are recommended for male patients.
2026-06-04 | Successful Sirolimus Therapy in Steroid-Refractory RAS-Associated Autoimmune Lymphoproliferative Disorder with Mosaic KRAS Mutation
Introduction Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective lymphocyte apoptosis caused by abnormalities in the FAS signaling pathway and presents with lymphadenopathy, splenomegaly, and autoimmune manifestations. RAS-associated autoimmune lymphoproliferative disorder (RALD) is classified as an ALPS-related disorder and is caused by somatic mutations in NRAS or KRAS, resulting in constitutive activation of the RAS signaling pathway. This leads to impaired apoptosis, abnormal lymphocyte proliferation, and autoimmune manifestations. Compared with classic ALPS, RALD may exhibit distinct clinical features such as mild monocytosis or juvenile myelomonocytic leukemia (JMML)-like findings, making accurate differential diagnosis essential. Although glucocorticoids are generally considered first-line therapy, optimal management strategies for glucocorticoid-refractory cases remain to be established. Case Presentation A two-year-old boy who had been diagnosed with autoimmune hemolytic anemia at eight months of age developed transient thrombocytopenia and nephrotic syndrome. His cytopenia was unresponsive to glucocorticoid therapy, and he became transfusion dependent. Genetic testing later identified a mosaic KRAS variant (p.Gly13Asp), leading to the diagnosis of RALD. Based on recent reports suggesting the possibility of efficacy for mTOR inhibitors in monogenic disorders characterized by immune dysregulation and lymphoproliferation, an investigator-initiated clinical trial using sirolimus was proposed and initiated after obtaining consent. After the introduction of sirolimus, the patient achieved transfusion independence. However, his clinical course was complicated by secondary hypogammaglobulinemia, which currently requires ongoing immunoglobulin replacement therapy. Discussion Sirolimus suppresses the activation and proliferation of T and B lymphocytes, thereby controlling pathological lymphoproliferation and autoimmune manifestations in RALD. This case highlights the clinical utility of sirolimus as a promising therapeutic option for glucocorticoid-refractory RALD.
2026-06-03 | Therapeutic Targeting of IL-17A-Driven PTGS2/NLRP3 Inflammasome Activation in Juvenile Myelomonocytic Leukemia.
Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myelodysplastic syndrome or myeloproliferative disorder for which hematopoietic stem cell transplantation remains the only curative option; however, outcomes are particularly poor in patients harboring PTPN11 (encodes SHP2 phosphatase) mutations. Using a Shp2E76K/+ JMML mouse model, we identify a pathogenic IL-17A/PTGS2/NLRP3 signaling axis that drives bone marrow inflammation, suppresses antitumor immunity, and promotes leukemic progression. Shp2E76K/+ mice exhibited profound immune dysregulation, characterized by expansion of regulatory T cells (Tregs), increased T-cell exhaustion, and impaired cytotoxic function with reduced CD4⁺ and CD8⁺ T-cell frequencies. Mechanistically, mutant macrophages upregulated IL-17A, triggering NLRP3 inflammasome activation, PTGS2 induction, caspase-1 cleavage, and IL-1β maturation, thereby amplifying inflammatory signaling within the marrow niche. Therapeutically, IL-17A neutralization suppressed inflammasome activity, while combined inhibition of NLRP3 and PTGS2 restored cytotoxic T-cell function, reduced systemic and marrow inflammation, reversed myeloproliferation, and significantly prolonged survival in Shp2E76K/+ mice. Importantly, ex vivo treatment of primary JMML patient samples with dual NLRP3/PTGS2 inhibition combined with MEK blockade significantly reduced leukemic progenitor colony formation, supporting translational relevance. In patient-derived xenograft models of PTPN11-mutant JMML, dual NLRP3/PTGS2 inhibition combined with MEK blockade most effectively reduced leukemic burden, decreased human CD45⁺ engraftment, and depleted leukemic CD34⁺CD38⁺ progenitors and GMPs while restoring MEP populations, resulting in significantly improved overall survival. Together, these findings establish IL-17A/PTGS2/NLRP3 signaling as a central driver of immune suppression and myeloid expansion in PTPN11-mutant JMML and highlight combinatorial anti-inflammatory targeting as a promising therapeutic strategy for this high-risk disease.
2026-05-27 | Molecular Advances in Juvenile Myelomonocytic Leukemia and Associated RASopathy.
Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive myeloproliferative neoplasm of early childhood characterized by constitutive activation of the RAS-MAPK signaling pathway. RASopathies are a heterogeneous group of complex genetic disorders arising from germline mutations that dysregulate RAS-MAPK signaling. Noonan syndrome, CBL syndrome, and neurofibromatosis type 1 (NF1) are the three major RASopathies predisposing to JMML. More than 90% of JMML cases harbor germline or somatic mutations in one of five canonical driver genes-PTPN11, NRAS, KRAS, NF1, or CBL-establishing JMML as the prototypical malignant manifestation of RASopathy biology. The fifth edition of the World Health Organization Classification of Tumours reclassified JMML as a myeloproliferative neoplasm while the International Consensus Classification adopted JMML under pediatric and/or germline mutation-associated disorders, introducing a JMML-like category for cases lacking five canonical mutations but harboring emerging drivers such as SH2B3::LNK alterations and ALK::ROS1 fusions. The distinction between germline and somatic mutations profoundly influences prognosis: e.g., germline PTPN11-associated myeloproliferations and many germline CBL cases undergo spontaneous resolution, whereas somatic PTPN11- and NF1-mutated JMML is more aggressive and requires prompt allogeneic hematopoietic stem cell transplantation. DNA methylation profiling has emerged as the most robust prognostic framework, with consensus defining high-, intermediate-, and low-methylation subgroups that independently predict outcome. Both genotype and DNA methylation subclassification have been integrated into clinical decision-making, incorporating pretransplant azacitidine, watch-and-wait approaches for favorable-risk patients, and emerging targeted therapies including MEK inhibitors. This review synthesizes recent advances in understanding JMML as a bona fide RASopathy; provides a diagnostic algorithm, molecular landscapes, and prognostic models; and highlights opportunities for molecularly targeted therapeutic intervention.
2026-05-06 | The role of RAS mutations in leukemia progression, differentiation, and drug resistance.
Mutations in the RAS gene family (NRAS, KRAS) are critical drivers of late-stage acute myeloid leukemia (AML) progression. They are frequently detected in relapsed/refractory AML and AML transformed from myelodysplastic syndrome (MDS). Occurring as late-stage genetic events, RAS mutations synergize with early drivers to promote leukemogenesis. While mutually exclusive with FLT3-ITD mutations, they coexist with KIT, RUNX1, CEBPA mutations and MLL rearrangements. Granulocyte-monocyte progenitors (GMPs) serve as the cellular origin for RAS-mutant leukemia stem cells (LSCs). Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.
cell therapies
2025-11-05 | HAPLOIDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH POST-TRANSPLANT CYCLOPHOSPHAMIDE FOR CHILDREN WITH JUVENILE MYELOMONOCYTIC LEUKEMIA
transplant.One NRAS-mutated patient only received 6 courses of azacitidine and had resolution of disease without HSCT.Overall survival in 10 patients, with a median FU time of 3yr9mo since diagnosis and 3yr3mo after first HSCT (n=9) is 90%.(Two patients are within 1 year from first or second HSCT and one is prior to first HSCT and thus outcome cannot yet be reported).Conclusions: Overall survival in the Dutch cohort is excellent.Three of four patients with relapse after first transplant and more than 1yr after a second (or third) transplant are disease free.
2025-11-03 | Clinical outcome of hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia: A Single center in China
Abstract Objective: To evaluate the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in the treatment of juvenile myelomonocytic leukemia (JMML). Methods: A retrospective analysis was conducted on 142 JMML pediatric patients who underwent HSCT at our center from October 2018 to February 2025. The median age at transplantation was 33 months (range: 11–99 months). The transplantation methods comprised: haploidentical + cord blood complementary transplantation (CT) (83 cases), haploidentical donor lymphocyte infusion (DLI) + cord blood transplantation (DLI+CB) (19 cases), unrelated donor transplantation (MUD) (27 cases), haploidentical post-transplant cyclophosphamide (PTCy) transplantation (PBSCT) (9 cases), and haploidentical ex vivo T-cell-depleted (TDH) transplantation (4 cases). In the CT group, haploidentical peripheral blood stem cells (PBSCs) (MNC >15×10^8/kg) were infused on day 0. GVHD prophylaxis included cyclophosphamide on days +3 and +4, along with FK506 and mycophenolate mofetil (MMF). Unrelated cord blood was infused on day +6. For the DLI + CB group, haploidentical donor lymphocytes (4–8×10^8/kg) were administered on day -11, followed by conditioning with CY, BU, TT, and Flu from day -8 to -3. Unrelated cord blood was infused on day 0, the unrelated cord blood matching requires ≥7/10 HLA locus , and Kir assay was carried out at the same time. Cord blood with Haplotype Cen-Bx was preferred. GVHD prophylaxis included FK506 and MMF. Among the 27 unrelated donor transplantations, 25 were 10/10 HLA-matched, and 2 were 9/10 matched. The conditioning regimen consisted of BU+CY+TT+Flu±ATG-F, with a median PBSC mononuclear cell count of 8.6×10^8/kg infused on day 0. GVHD prophylaxis included FK506 and MMF. The haploidentical PTCy group followed the same infusion strategy as the complementary group. Four patients received ex vivo αβT-cell-depleted (TDH) transplantation without routine post-transplant immunosuppression. Results: With a median follow-up of 45 months (range: 7–81 months). The overall survival (OS) and leukemia-free survival (LFS) rates for all 142 patients were 92% and 91.7%, respectively. All 4 TDH transplant patients survived. The OS rates were 97.5% for the CT group (83 cases), 82.3% for the DLI + CB group (19 cases), 86.7% for the MUD group (27 cases), and 77.8% for the haploidentical PTCy group (9 cases). No statistically significant differences were observed between groups (P=0.057). The cumulative incidence of grade II–IV acute GVHD was 16.2% (23 cases), including 7 cases of grade III–IV. Chronic GVHD occurred in 18.3% (26 cases), primarily involving the skin, with 2 cases affecting the lungs, 1 the joints, and 2 the liver. Post-transplant viral reactivation was mostly transient, with HHV6 being the most common. Two cases progressed to viral encephalitis. Other viral reactivations included 5 cases of CMV and 2 of adenovirus. Three cases of veno-occlusive disease (VOD) were reported, 2 of which were mild. Conclusion: HSCT demonstrates significant clinical efficacy and relative safety in treating JMML. Different transplantation methods yielded high survival rates, with complementary transplantation showing particular advantages. TDH transplantation exhibited promising preliminary results, warranting further exploration.
2025-08-04 | Tandem CD19/CD22 CAR T-cells as potential therapy for children and young adults with high-risk r/r B-ALL.
Chimeric antigen receptor (CAR) T-cells targeting CD19 have shown impressive outcomes in refractory/relapsed B-cell acute lymphoblastic leukaemia (r/r B-ALL); however, frequent relapse demands multi-targeted approaches. We report Spanish clinical data on the safety and efficacy of tandem anti-CD19/CD22 CAR T-cells administered on a compassionate use basis in a cohort of 10 heavily pretreated paediatric, adolescent, and young adult (AYA) patients with r/r B-ALL. Most (9/10) of the patients had relapsed B-ALL, 7 having received previous anti-CD19 CAR T-cell therapy and 6 haematopoietic stem cell transplantation (HSCT). Two patients had Down syndrome. Increased high-grade CRS/ICANS and proinflammatory markers (IL-6, LDH and ferritin) correlated with patients with a high tumour burden (TB) before lymphodepletion. Complete remission on day +28 post-infusion was achieved in 8/10 patients (7 with MRD-), and 5/7 patients received HSCT as consolidative therapy within three months post-infusion. Two patients with early relapse after tandem anti-CD19/CD22 CAR received rescue therapy and HSCT. At the 18-month follow up, overall survival (OS) was 70% (95% CI, 47%-100%). Tandem anti-CD19/CD22 CAR T-cell administration combined with consolidative HSCT is a promising therapeutic approach, though managing bridging therapy and reducing the TB prior to infusion remain key challenges (REALL_CART trial, NCT06709469, EudraCT 2023-509723-41-01). This work was supported by a grant from the Instituto de Salud Carlos III to APM PI22/01226, two grants from CRIS Cancer Foundation to Beat Cancer as part of the projects "Advanced Cell Therapy Unit Hospital Universitario La Paz" and JM "Proyecto Mateo: CAR T-cell therapy for juvenile myelomonocytic leukaemia" and "Terapia avanzada CAR-T CD19/CD22", Ayuda Nominativa de la Consejería de Investigación, Comunidad de Madrid, Spain. Work in MI lab was funded by a grant from the Spanish Ministry of Science and Innovation (PID2020-114148RB-I00). VGG was granted with Río Hortega (AES 2022 exp. Nº. CM22/00078) and Juan Rodés (AES 2024 exp. Nº. JR24/00003) contracts from the Carlos III Health Institute (ISCIII) through the European Funds of the Recovery, Transformation and Resilience Plan and financed by the European Union NextGenerationEU.
2025-06-04 | [Genetic and clinical characteristics of children with RAS-mutated juvenile myelomonocytic leukemia].
To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
2025-05-09 | Successful Haplo-hematopoietic Stem Cell Transplantation for Juvenile Myelomonocytic Leukemia in a Child with Underlying Thrombocytopenia-Absent Radius Syndrome: A Unique Case
Background: Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital disorder characterized by bilateral radial aplasia with preserved thumbs and early-onset thrombocytopenia. While hematologic and skeletal abnormalities are hallmarks of the condition, its association with hematologic malignancies is exceedingly rare, with only a few reported cases of leukemia. Juvenile myelomonocytic leukemia (JMML) is an uncommon pediatric myelodysplastic/myeloproliferative neoplasm frequently linked to RAS pathway mutations. The co-occurrence of JMML in a patient with TAR syndrome has not been previously documented. Case Presentation: We report the case of a male infant diagnosed with TAR syndrome based on clinical features and molecular confirmation of a homozygous RBM8A c.-21G>A mutation. The patient presented initially with persistent thrombocytopenia, skeletal deformities, and neonatal sepsis-like symptoms. At two years of age, he developed pancytopenia and progressive splenomegaly. Bone marrow examination and molecular studies confirmed JMML with a pathogenic NF1 mutation. He underwent successful haploidentical hematopoietic stem cell transplantation (HSCT) from a sibling donor, following a conditioning regimen of melphalan, treosulfan, cyclophosphamide, and anti-thymocyte globulin. The patient achieved full donor chimerism and hematologic remission with stable engraftment. Conclusion: This case represents, to our knowledge, one of the very few—if not the first—reported instances of successful HSCT for JMML in a patient with TAR syndrome. It underscores the importance of vigilant surveillance in TAR patients for potential malignant transformation and demonstrates the curative potential of HSCT in complex congenital and hematologic overlap syndromes.
antibodies
2026-03-04 | Data from Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia
<div>Abstract<p>Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible <i>Ptpn11</i><sup><i>E76K</i></sup> mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML.</p>Significance:<p>Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic <i>PTPN11</i> mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities.</p><p><a href="https://aacrjournals.org/bloodcancerdiscov/article-abstract/doi/10.1158/2643-3230.BCD-26-0006" target="_blank"><i>See related commentary by Miao and Xu, pp. 168</i></a></p></div>
2026-02-17 | Prevention of relapse of juvenile myelomonocytic leukemia (JMML) by inhibition of immune checkpoint CD47
Juvenile myelomonocytic leukemia (JMML) is an aggressive childhood myeloid malignancy driven by RAS pathway mutations, marked by clonal expansion and tissue infiltration of myeloid cells, including macrophages. This study investigated the role of macrophage polarization, phagocytic function, and CD47-mediated immune evasion in JMML pathogenesis. Analysis of human PTPN11-mutated JMML spleen samples revealed an enrichment of pro-inflammatory M1-like macrophages compared to KRAS-mutated cases and controls. Both human JMML macrophages and murine Ptpn11-mutant macrophages retained phagocytic capacity, with M1-like subsets exhibiting the highest activity. CD47, an immune checkpoint ligand that inhibits phagocytosis, was overexpressed in JMML cells, and its blockade enhanced macrophage-mediated clearance in vitro. In a patient-derived xenograft model, CD47 inhibition with magrolimab reduced splenic leukemia burden but showed limited efficacy in the bone marrow, with no synergistic effect observed when combined with azacitidine. These findings demonstrate that JMML macrophages remain functionally active and contribute to disease-associated inflammation, while CD47 blockade offers partial therapeutic benefit. Our study underscores the complex interplay between macrophage polarization, immune evasion, and inflammatory signaling in JMML, providing insights for future targeted therapies.
2025-12-22 | Juvenile myelomonocytic leukemia stem cells are sensitive to NK cell-mediated lysis and express targetable antigens.
Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm for which hematopoietic stem cell transplantation is the only curative treatment. Innovative therapies are needed to address high rates of morbidity, treatment-related mortality, and relapse. Monoclonal antibodies and adoptive cell transfer of natural killer (NK) cells or T cells are approved or being investigated for other myeloid leukemias; however, their activity against JMML warrants further investigation. In this study, we hypothesized that NK cells may effectively target JMML tumor cells. Mass cytometry was used to evaluate the expression of NK cell-activating and -inhibitory ligands and candidate target antigens on the monocytic and stem cell subsets of JMML. Monocytes from healthy donors and monocytic subsets of JMML were similar in NK cell ligand expression, and JMML monocytes were resistant to NK cell cytotoxicity in vitro. However, NK cells effectively controlled proliferation of JMML colony-forming cells. CD34+CD38- JMML stem cells express a broad repertoire of NK cell ligands similar to that of acute myeloid leukemia stem cells; and CD33, CD44, and CD47 were expressed by both CD34+CD38- stem cells and CD34+CD38+ progenitors in JMML. This suggests that JMML may be responsive to NK cell-mediated activity, and that targeting CD33, CD44, or CD47 may facilitate eradication of JMML.
2025-12-05 | Molecular Plasticity Results in Oncofetal Reprogramming and Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia.
Persistent fetal gene expression in childhood neoplasms is usually explained by a maturation block originating in the prenatal phase. In contrast, reactivation of fetal genes in adult malignancies is considered a consequence of oncofetal reprogramming (OFR) and is associated with aggressive disease. By reconstructing epigenetic ontogeny in juvenile myelomonocytic leukemia (JMML), we identified a postnatal maturation state of JMML stem cells with high transcriptional plasticity indicative of OFR in high-risk disease. Similarly, postnatal activation of oncogenic signaling by inducible Ptpn11E76K mutation in mice triggered molecular plasticity and reactivation of fetal gene expression. Integrative multi-omics analysis revealed aberrant CD52 expression as a feature of high-risk JMML stem cells. Anti-CD52 treatment depleted JMML stem cells and blocked disease propagation in xenograft models. Our results challenge the prevailing maturation block model of pediatric leukemogenesis and establish RAS-associated stem cell plasticity as a determinant of OFR and potential therapeutic vulnerabilities in high-risk JMML. Persistent fetal gene expression in pediatric malignancies is considered a consequence of prenatal maturation blockade. In this study, we demonstrate that oncogenic PTPN11 mutations enhance cellular plasticity. This leads to partial restoration of fetal molecular programs, creating new therapeutically exploitable vulnerabilities. See related commentary by Miao and Xu, pp. 168.
2025-11-07 | Novel humanized loss-of-function NF1 mouse model of juvenile myelomonocytic leukemia.
Juvenile myelomonocytic leukemia (JMML) is a fatal pediatric cancer characterized by classical features such as splenomegaly, monocytosis, and granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity, with RAS pathway mutations being the major drivers. Mutations causing loss-of-function of the Neurofibromin 1 gene (NF1LOF) occur in ∼20% of patients with JMML. NF1LOF drives upregulation of RAS/MAPK/PI3K pathways that leads to aggressive proliferation/differentiation of immature myeloid cells. Hematopoietic stem cell transplantation is the only curative option, but relapse occurs in ∼50% of patients, indicating an urgent need for novel and targeted therapeutic strategies. However, low patient sample availability and a lack of reliable disease models have made it difficult to study and treat JMML. Using CRISPR/Cas9, we have generated NF1LOF in human umbilical cord blood-derived hematopoietic stem and progenitor cells (HSPCs). We achieved a high gene knockout rate of ∼89% and concomitant loss of NF1 protein in the modified HSPCs. Importantly, NF1LOF cells displayed marked GM-CSF hypersensitivity in in vitro colony-forming unit assays, mirroring JMML. When transplanted into NSG-SGM3 mice, they caused rapid lethality (median survival of 32 days), myeloid expansion, tissue infiltration (spleen, liver, and lungs), and specific upregulation of RAS/MAPK pathway and STAT5 genes, consistent with patient profiles. This first humanized NF1LOF mouse model recapitulates key JMML features, enabling investigation of disease mechanisms and targeted therapies.
oligonucleotides
2023-06-14 | RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia
RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS-mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.
2021-03-11 | Revisiting the Relationship Between Alzheimer’s Disease and Cancer With a circRNA Perspective
Increasing evidence indicates an association between the incidence of Alzheimer's disease (AD) and cancer development. Despite advances being made by comparisons from epidemiological studies, common pathways and molecular mechanisms, little is known about the identities of the circular RNAs (circRNAs) involved in the development and progression of these two pathologies and their possible correlations. The aim of this study was to explore the circRNA relationship between AD and cancer.In this investigation, circRNAs that were significantly dysregulated in AD or associated with AD diagnosis, clinical dementia severity, and neuropathological severity, were examined in a large panel of 28 cancer types. On the basis of shared abnormal circRNAs in AD and cancers, we constructed a circRNA-micro RNA (miRNA)-messenger RNA (mRNA) network by leveraging experimentally identified miRNA-circRNA and miRNA-mRNA interactions from crosslinking-immunoprecipitation sequencing data.An inverse correlation of expression pattern was found in acute myeloid leukemia, juvenile myelomonocytic leukemia, renal cell carcinoma, and myelofibrosis. CircRNAs associated with AD diagnosis and clinical severity demonstrated negative correlation in more cancer types. Notably, differentially expressed candidate circRNAs in temporal lobe epilepsy were not associated with any cancers. Gene Ontology and KEGG pathway analysis suggested the circRNA-regulated genes are significantly associated with interleukin-12-mediated signaling and viral response. CircPICALM, circRTN4 and circMAN2A1 are the hub nodes in the circRNA-miRNA-target network.Our results indicated the relevance of inflammation signaling as a common pathogenesis shared by cancer and AD and provided novel insight for therapeutics targeting circRNAs.
2021-01-04 | Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by proinflammatory cytokine–induced lncRNA Morrbid
Diabetes mellitus (DM) is a risk factor for cancer. The role of DM-induced hyperglycemic (HG) stress in blood cancer is poorly understood. Epidemiologic studies show that individuals with DM are more likely to have a higher rate of mutations in genes found in pre-leukemic hematopoietic stem and progenitor cells (pre-LHSPCs) including TET2. TET2-mutant pre-LHSPCs require additional hits to evolve into full-blown leukemia and/or an aggressive myeloproliferative neoplasm (MPN). Intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the extrinsic factors are poorly understood. Using a mouse model carrying Tet2 haploinsufficiency to mimic the human pre-LHSPC condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces hyperglycemia and type 1 DM, we show that the compound mutant mice developed a lethal form of MPN and/or acute myeloid leukemia (AML). RNA-Seq revealed that this was due in part to upregulation of proinflammatory pathways, thereby generating a feed-forward loop, including expression of the antiapoptotic, long noncoding RNA (lncRNA) Morrbid. Loss of Morrbid in the compound mutants rescued the lethality and mitigated MPN/AML. We describe a mouse model for age-dependent MPN/AML and suggest that hyperglycemia acts as an environmental driver for myeloid neoplasms, which could be prevented by reducing expression levels of the inflammation-related lncRNA Morrbid.
2020-12-30 | Molecular and phenotypic diversity of <I>CBL</I>-mutated juvenile myelomonocytic leukemia
Mutations in the CBL gene were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to patients with other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells. Here, we systematically studied a large cohort of 33 JMML patients with CBL mutations and found that this disease is highly diverse in presentation and overall outcome. Moreover, we discovered somatically acquired CBL mutations in 15% of pediatric patients who presented with more aggressive disease. Neither clinical features nor methylation profiling were able to distinguish patients with somatic CBL mutations from those with germline CBL mutations, highlighting the need for germline testing. Overall, we demonstrate that disease courses are quite heterogeneous even among patients with germline CBL mutations. Prospective clinical trials are warranted to find ideal treatment strategies for this diverse cohort of patients.
2019-01-30 | Sipa1 deficiency-induced bone marrow niche alterations lead to the initiation of myeloproliferative neoplasm.
Mutations of signal-induced proliferation-associated gene 1 (SIPA1), a RAP1 GTPase-activating protein, were reported in patients with juvenile myelomonocytic leukemia, a childhood myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Sipa1 deficiency in mice leads to the development of age-dependent MPN. However, Sipa1 expression in bone marrow (BM) microenvironment and its effect on the pathogenesis of MPN remain unclear. We here report that Sipa1 is expressed in human and mouse BM stromal cells and downregulated in these cells from patients with MPN or MDS/MPN at diagnosis. By using the Sipa1-/- MPN mouse model, we find that Sipa1 deletion causes phenotypic and functional alterations of BM mesenchymal stem and progenitor cells prior to the initiation of the MPN. Importantly, the altered Sipa1-/- BM niche is required for the development of MDS/MPN following transplantation of normal hematopoietic cells. RNA sequencing reveals an enhanced inflammatory cytokine signaling and dysregulated Dicer1, Kitl, Angptl1, Cxcl12, and Thpo in the Sipa1-/- BM cellular niches. Our data suggest that Sipa1 expression in the BM niche is critical for maintaining BM niche homeostasis. Moreover, Sipa1 loss-induced BM niche alterations likely enable evolution of clonal hematopoiesis to the hematological malignancies. Therefore, restoring Sipa1 expression or modulating the altered signaling pathways involved might offer therapeutic potential for MPN.
other
2025-02-20 | Noonan Syndrome, Cancer Risk, and Growth Hormone Treatment.
Cancer can occur in patients with Noonan syndrome (NS). Review of English literature revealed that myeloproliferative diseases are the most prevalent, followed by intracranial tumours. There is no genotype phenotype relationship between germline pathogenic variants so it not possible to precisely predict cancer risk in NS, however some PTPN11 variants are exclusively detected in juvenile myelomonocytic leukemia and are not observed in other types of cancer. Among patients on growth hormone, cancer development was reported in seven patients with genetically confirmed NS, and five patients with clinically diagnosed NS. However, information on growth hormone dose, timing, and follow-up characteristics in these cases is heterogeneous. In the light of current data, especially in cases for whom growth hormone therapy is considered, the diagnosis should be genetically confirmed, and the results of genetic analysis should be compared with the cases reported in the literature. Families should be informed about possible cancer risk and in cases predisposing to juvenile myelomonocytic leukemia, early initiation of growth hormone therapy should be avoided.
2024-09-18 | Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.
Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n = 58) than in the pre-DF era (31% vs. 13%, p = .04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p = .04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p < .01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p = .01) and juvenile myelomonocytic leukemia (OR = 8.98, p = .04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.
2022-08-02 | Overexpression, biochemical characterization, and anticancer activates of L-asparaginase from Bacillus subtilis
L-asparaginases convert L-asparagine into L-aspartate and ammonia. The L-asparaginase from Bacillus subtilis was cloned and expressed in the E. coli strain BL21(DE3)pLysS in the current study. Using glutathione sepharose 4B column chromatography, the L-asparaginase enzyme was uniformly purified 173.34 times, with a final specific activity of 1769.13 IU/mg protein and a yield of 56.14%. The isolated enzyme was identified as a 36 kDa polypeptide chain by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The immobilized enzyme was placed on top of the Ca alginate beads. The immobilized enzyme is quite stable and retains the majority of its activity at 4 °C (74 percent). The enzymatic and structural characteristics of free and immobilized recombinant L-asparaginase were studied. The activity of the free enzyme peaked after 30 min of incubation at pH 8.0 and 45 °C. After 30 minutes at 50 °C, the immobilized enzyme showed its peak activity at a pH of 8.5. The refined enzyme's amino acid makeup was identified. An enzyme that heals leukemia, Bacillus subtilis L-asparaginase, can be successfully mass-produced using this technique.
2019-02-01 | Targeting cell-bound MUC1 on myelomonocytic, monocytic leukemias and phenotypically defined leukemic stem cells with anti-SEA module antibodies
Cell surface molecules aberrantly expressed or overexpressed by myeloid leukemic cells represent potential disease-specific therapeutic targets for antibodies. MUC1 is a polymorphic glycoprotein, the cleavage of which yields two unequal chains: a large extracellular α subunit containing a tandem repeat array bound in a strong noncovalent interaction to a smaller β subunit containing the transmembrane and cytoplasmic domains. Because the α-chain can be released from the cell-bound domains of MUC1, agents directed against the α-chain will not effectively target MUC1+ cells. The MUC1 SEA (a highly conserved protein module so called from its initial identification in a sea urchin sperm protein, in enterokinase, and in agrin) domain formed by the binding of the α and β chains represents a stable structure fixed to the cell surface at all times. DMB-5F3, a partially humanized murine anti-MUC1 SEA domain monoclonal antibody, was used to examine MUC1 expression in acute myeloid leukemia (AML) and was found to bind acute myelomonocytic and monocytic leukemia (AML-M4 and AML-M5) cell lines. We also examined monocytic neoplasms freshly obtained from patients including chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, which were found to uniformly express MUC1. CD34+/lin-/CD38- or CD38+ presumed leukemic stem cell populations from CD34+ AML and CD34-CD38- or CD38+ populations from CD34- AML were also found to express MUC1, although at low percentages. Based on these studies, we generated an anti-MUC1 immunotoxin to directly gauge the cytotoxic efficacy of targeting AML-bound MUC1. Using single-chain DMB-5F3 fused to recombinant gelonin toxin, the degree of AML cytotoxicity was found to correlate with MUC1 expression. Our data support the use of an anti-MUC1 SEA module-drug conjugates to selectively target and inhibit MUC1-expressing myelomonocytic leukemic cells.
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Drug Discovery Landscape
2 orphan drug designations for Juvenile myelomonocytic leukemia, including 1 approved therapy.
2 orphan drug designations for Juvenile myelomonocytic leukemia, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
azacitidine [Vidaza] | small molecules | FDA | 2021-07-28 | 2022-05-20 | Celgene Corporation (a Bristol-Myers Squibb Company) |
Granulocyte-macrophage colony-stimulating factor, recombinant | proteins | EMA | 2002-03-18 | — | British Biotech Pharmaceuticals Limited |
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