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RNA seq analysis of MEK inhibitor in combination with 5-azacitidine treated Shp2E76K/+ driven JMML mice

ABSTRACT: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic and myeloproliferative neoplasm of childhood. Excessive proliferation of monocytes into the liver, spleen, lungs, and skin is frequently observed at presentation. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy with a probability of event-free survival at 5-years of approximately 50%. The molecular hallmark of JMML is hyperactivation of the Ras/MAPK signaling pathway with the most common cause being mutations in the gene PTPN11, encoding the protein tyrosine phosphatase SHP2. Current therapeutic strategies in JMML include using MEK inhibitors such as trametinib and PD0325901 (PD-901) or the hypomethylating agent, 5-azactidine, but none of these are curative as monotherapy. In this study, utilizing a gain of function (GOF) Shp2E76K/+ murine model of JMML, we showed that the combination of PD-901 and 5-azacitidine reduced leukocytosis, monocytosis, and splenomegaly and reversed thrombocytopenia. Importantly, this drug combination significantly reduced leukemic hematopoietic stem and progenitor cells (HSC/Ps) in the Shp2E76K/+ mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE211278 | GEO | 2025/08/15

REPOSITORIES: GEO

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Inflammatory response in HSPC of PTPN11-mutated JMML

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Transcriptome and methylation analysis of JMML patients compare to healthy prenatal and postnatal samples.

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miRNA expression profiling of 21 JMML patients and 4 healthy donors

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Gene expression profiling in 38 JMML patients and 9 healthy donors (Validation cohort)

Project description:Juvenile myelomonocytic leukemia (JMML) is a very rare and aggressive stem cell disease that mainly occurs in young children. RAS activation constitutes the core component of oncogenic signaling. In addition, the leukemic blasts of a quarter of JMML patients present with monosomy 7 (-7), whereas more than half of the patients show enhanced age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care. This results in an event-free survival of 50 - 60%, indicating that novel molecular driven therapeutic options are urgently needed. Using gene expression profiling in an extensive series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. Interestingly, LIN28B overexpression was significantly correlated with higher HbF levels whereas patients with -7 seldom showed enhanced LIN28B expression. In line with LIN28Bâ??s role as mediator of fetal hematopoiesis, this explains the biology behind the observation that patients with -7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Finally, high LIN28B expression was associated with poor clinical outcome in our JMML patient series, but not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified LIN28B as a crucial molecular player at the heart of a novel fetal-like subgroup in JMML. Gene expression was measured on Affymetrix in 38 JMML patients and 9 healthy donors in a validation cohort.

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