MCL1 Haploinsufficiency Protects Mice From MYC-Induced Acute Myeloid Leukemia.

Abstract 764

Anti-apoptotic Bcl2 family genes have been implicated in the pathogenesis of acute myelogenous leukemia (AML), but the functional significance and relative importance of individual proteins (i.e. BCL2, BCL-XL, MCL1) remains poorly understood. We examined the expression of BCL2, BCL-X and MCL1 in primary human hematopoietic subsets and in leukemic blasts from AML patients, and found MCL1 transcripts were consistently expressed at high levels in all samples tested (100%, n=111). Mcl1 protein was also consistently expressed at high levels in myeloid leukemic blasts in a murine Myc-induced AML model, and we used this model to test the hypothesis that Mcl1 facilitates AML development by allowing myeloid progenitor cells to evade oncogene-induced cell death. Activation of Myc for seven days in vivo substantially increased myeloid lineage cells while hematopoietic stem, progenitor and B-lineage cells were depleted. Haploinsufficiency for Mcl1 (Mcl1flox/null) abrogated the development of AML (median survival 56 days vs. not reached), and deletion of a single allele of Mcl1 from fully transformed AML cells significantly prolonged the survival of transplanted mice. In contrast, the rapid lethality of disease (median survival 25 days) was restored by co-expression of Bcl2 with Myc in Mcl1flox/null cells. Together, these data demonstrate a critical and dose-dependent role for Mcl1 in AML pathogenesis and suggest that Mcl1 may be an ideal therapeutic target in patients with de novo AML.