Analyzing the therapeutic efficacy of navitoclax and MCL-1 inhibitors in juvenile myelomonyctic leukemia

Juvenile myelomonocytic leukemia (JMML) is a highly aggressive myeloid malignancy of early childhood, caused by constitutive RAS pathway activation and epigenetic deregulation. Most patients require hematopoietic stem cell transplantation but recently, the DNA methyltransferase inhibitor azacitidine was shown to have unprecedented activity against JMML, both in patients and in our xenograft model. Here we aim at investigating whether so-called BH3-mimetics can be used to treat JMML. For this, we are treating JMML xenograft mice with either ABT737 (a navitoclax analogue) or S63845, two BH3-mimetics inhibiting BCL-2/BCL-XL or MCL-1, respectively. In addition, we are analyzing whether low-dose azacitidine can sensitize JMML towards these drugs. While high-dose azacitidine showed efficient depletion of leukemic cells and, most importantly, leukemia-initiating cells (LICs), treatment with ABT737 resulted in a reduction of leukemic infiltrations but not LICs. In vitro, MCL-1 inhibition showed stronger cytotoxic activities on patient-derived JMML cells than BCL-2/BCL-XL inhibition.