MOZ Is Critical for MOZ/MLL-Fusion-Induced HoxA9/Meis1 Expression and Leukemia Development,

Abstract 3467

Monocytic leukemia Zinc finger (MOZ), a Myst-type histone acetyltransferase, is involved in chromosome translocations associated with FAB M4/M5 subtypes of acute myeloid leukemia (AML). We have shown that MOZ is critical for hematopoietic cell development and self-renewal of hematopoietic stem cells (HSCs). Recent reports suggest that hematopoietic and leukemic stem cells shares molecular basis for their self-renewal. To clarify the roles of endogenous MOZ in malignant hematopoiesis, we tested MOZ-deficient cells for leukemogenesis by leukemia-associated fusion genes such as MOZ-TIF2, MLL-AF10 and PML-RARa. Hematopoietic stem/progenitor cells (HSPCs), prepared with MOZ+/− or MOZ−/− fetal livers, were stimulated with SCF, IL-3, IL-6 and Osteopontin M for 1 day and infected with retrovirus encoding each fusion genes. Five days after infection, the infected cells were transplanted into recipient mice or cultured in methylcellulose medium with IL-3, SCF and GM-CSF. MOZ+/− HSPCs expressing MOZ-TIF2 or MLL-AF10 fusion gene formed colonies repeatedly and the recipient mice developed AML 2–3 month after transplantation. However, the MOZ−/− HSPCs expressing the MOZ/MLL-fusions showed neither colony-forming activity nor AML-inducing acyivity. On the other hand, when PML-RARa was introduced, both MOZ+/− and MOZ−/− cells showed continuous colony-forming activity. Expression of HoxA9 and Meis1 were high in MOZ+/− cells expressing MOZ/MLL-fusions, but they were very low in MOZ−/− cells expressing MOZ/MLL fusions. We have previously reported that expression of HoxA9 and Meis1 was significantly decreased in HSPCs of MOZ−/− fetal liver. When MOZ−/− HSPCs were stimulated in a condition without IL-6 prior to infection of MOZ-TIF2, the MOZ−/− cells acquired ability to generate colonies serially. In this condition, high HoxA9 expression was induced in the MOZ−/− cells. However, Meis1 expression was low and AML was not induced in recipient mice. These results indicate that endogenous MOZ plays critical roles in MOZ/MLL-fusion-induced AML and in HoxA9 and Meis1 gene expression.