Antileukemic activity of the azacitidine in a xenograft model of juvenile myelomonocytic leukemia

Introduction: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood. Patients present with hepatosplenomegaly, lymphadenopathy and skin rash, and peripheral blood analysis reveals monocytosis and the presence of myeloid precursors. Clinical signs are caused by organ infiltration of proliferating monocytes and granulocytes. JMML cells are characterized by a deregulated activation of the RAS signaling pathway as a result of mutations in KRAS, NRAS, NF1, PTPN11 (encoding SHP2) or CBL. When left untreated, most patients die from respiratory failure due to leukemic lung infiltration. The only curative treatment of JMML so far is allogeneic hematopoietic stem cell transplantation (HSCT), with an overall survival of 60%. DNA hypermethylation in JMML cells is associated with an aggressive disease course and poor outcome. This suggests a key role of epigenetic modifications in JMML pathophysiology. Accordingly, the clinical efficacy of epigenetic treatment with the DNA methyltransferase inhibitor azacitidine was recently demonstrated in a retrospective JMML case series (Cseh et al, Blood 2015). A clinical trial using azacitidine as a front-line therapy is ongoing.