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
485 drug discovery papers about Juvenile myelomonocytic leukemia, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
485 drug discovery papers about Juvenile myelomonocytic leukemia, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-04-15 | Identification of novel therapeutic approaches in juvenile myelomonocytic leukemia (JMML)
Juvenile myelomonocytic leukemia (JMML) is a rare childhood myeloid neoplasm driven by RAS pathway mutations and characterized by aberrant monocytic and granulocytic proliferation. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative therapy, but relapse is frequent, particularly in patients with PTPN11 mutations. To identify novel therapies, we combined ex vivo drug screening of primary patient samples with mechanistic studies of immune escape in PTPN11-mutant JMML. Ex vivo screening of 173 small molecules revealed heterogeneous, patient-specific sensitivities, with selective activity of FLT3 inhibitors, HSP90 inhibitors, and BCL-2 familytargeting compounds. The NEDD8-activating enzyme inhibitor pevonedistat induced apoptosis in vitro but failed to reduce leukemic burden in patient-derived xenografts (PDX), highlighting the importance of in vivo validation. HDAC, proteasome, and polo-like kinase inhibitors showed higher JMML-specific activity, defining actionable therapeutic pathways. High-dimensional immune profiling of primary PTPN11-mutant JMML samples and revealed expansion of stem and myeloid populations, depletion of T and NK cells, and upregulation of multiple immune checkpoints. in MxCre;Ptpn11D61Y/+ mice, among these, CD39 and CD73 were enhanced by GM-CSF and directly regulated by oncogenic SHP2. Ptpn11D61Y/+ myeloid cells suppressed T cell activation, an effect reversed by CD39 inhibition with POM-1, which also induced leukemic cell apoptosis. In vivo, POM-1 partially reduced spleen size and reshaped the immune microenvironment, underscoring the dual therapeutic potential of targeting the adenosine pathway. These findings highlight patient-specific drug sensitivities and immune escape mechanisms in JMML, supporting a combined approach of targeted therapy and immune modulation for future precision treatments.
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.
2026-04-15 | Identification of novel therapeutic approaches in juvenile myelomonocytic leukemia (JMML)
Juvenile myelomonocytic leukemia (JMML) is a rare childhood myeloid neoplasm driven by RAS pathway mutations and characterized by aberrant monocytic and granulocytic proliferation. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative therapy, but relapse is frequent, particularly in patients with PTPN11 mutations. To identify novel therapies, we combined ex vivo drug screening of primary patient samples with mechanistic studies of immune escape in PTPN11-mutant JMML. Ex vivo screening of 173 small molecules revealed heterogeneous, patient-specific sensitivities, with selective activity of FLT3 inhibitors, HSP90 inhibitors, and BCL-2 familytargeting compounds. The NEDD8-activating enzyme inhibitor pevonedistat induced apoptosis in vitro but failed to reduce leukemic burden in patient-derived xenografts (PDX), highlighting the importance of in vivo validation. HDAC, proteasome, and polo-like kinase inhibitors showed higher JMML-specific activity, defining actionable therapeutic pathways. High-dimensional immune profiling of primary PTPN11-mutant JMML samples and revealed expansion of stem and myeloid populations, depletion of T and NK cells, and upregulation of multiple immune checkpoints. in MxCre;Ptpn11D61Y/+ mice, among these, CD39 and CD73 were enhanced by GM-CSF and directly regulated by oncogenic SHP2. Ptpn11D61Y/+ myeloid cells suppressed T cell activation, an effect reversed by CD39 inhibition with POM-1, which also induced leukemic cell apoptosis. In vivo, POM-1 partially reduced spleen size and reshaped the immune microenvironment, underscoring the dual therapeutic potential of targeting the adenosine pathway. These findings highlight patient-specific drug sensitivities and immune escape mechanisms in JMML, supporting a combined approach of targeted therapy and immune modulation for future precision treatments.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles 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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