Mouse Models of Pediatric Acute Megakaryoblastic Leukemia Reveal Novel Therapeutic Vulnerabilities [DSP798]

Pediatric acute megakaryoblastic leukemia (AMKL) is an aggressive blood cancer associated with poor therapeutic response and high mortality. We developed CBFA2T3-GLIS2-driven mouse models of AMKL that recapitulate the phenotypic and transcriptional signatures of the human disease. We show that CBFA2T3-GLIS2 and GLIS2 modulate similar transcriptional networks. Oncogenic RAS cooperates with GLIS2 to trigger AMKL, enhancing the penetrance and decreasing the latency of CBFA2T3-GLIS2-dependent AMKL. We find that the FDA-approved drug pyrvinium pamoate, a GLI protein inhibitor, can be repurposed to impair CBFA2T3-GLIS2 levels and promote AMKL cell death. In addition, consistent with our findings that both CBFA2T3-GLIS2 and GLIS2 alter the expression of numerous BH3-only proteins, murine and patient-derived AMKL cells are sensitive to the BCL-2 inhibitor navitoclax. We observe a striking synergistic response to combined treatment with pyrvinium pamoate and navitoclax, suggesting a novel therapeutic option for pediatric patients suffering from CBFA2T3-GLIS2-driven AMKL. Overall design: Comparative gene expression analysis of RNA-seq data from leukemic BM cells expressing CBFA2T3-GLIS2 or BM cells from healthy mice. BM cells were sorted based on the expression of mCherry (MIC), CD41, c-Kit, and depleted for Gr1, CD3, B220 and Ter119.