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:
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.
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.
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
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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