Modulation of Navitoclax Sensitivity by Dihydroarteminisin-Mediated MCL-1 Repression. Mus musculus

Poor prognosis BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1. However, the survival of most normal blood cells (e.g. progenitors, lymphocytes, and granulocytes) and other normal cell types (e.g. cardiomyocytes and neurons) are also exquisitely dependent on Mcl-1 gene expression, suggesting that effective therapeutic inhibition of MCL-1 could be acutely toxic, especially when combined with standard chemotherapy. Therefore, as an alternative to MCL-1 inhibition, we have identified dihydroarteminisin (DHA), a water-soluble metabolite of the anti-malarial arteminisin, which induces the down-modulation of MCL-1 protein expression by triggering an endoplasmic reticulum stress response. The DHA induced repression of MCL-1 expression renders leukemic cells highly sensitive to synergistic cell death induced by BH3-mimetic agents such as navitoclax (ABT-263) in a mouse model of BCR-ABL+ B-ALL. Furthermore, DHA also synergizes with navitoclax in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL. These data demonstrate that combining DHA with BH3-mimetic agents can improve therapeutic response in poor prognosis leukemia. Overall design: We used microarrays to compare the DHA treatement to controls in mice.