Loss of the Inv(16) Oncogene Eliminates Leukemia from the Blood and Spleen, but not the Bone Marrow.

Inversion of chromosome 16 [inv(16)] is one of the most common chromosomal rearrangements in Acute Myeloid Leukemia (AML) and generates the fusion gene , which initiates leukemogenesis. Patients with inv(16) at diagnosis invariably have the rearrangement at relapse, leading to the assumption that is required after leukemic transformation. However, this has yet to be shown experimentally. Using a knock-in mouse that allows for deletion of after leukemia development, we found that loss of the fusion gene increased apoptosis and decreased colony growth . Interestingly, 5-20% of the colonies had successfully deleted . To test the role of , we used an inducible shRNA knockdown (KD) construct against the fusion gene. We found that decreased expression eliminated leukemia cells from the peripheral blood and spleen, but not the bone marrow, despite these cells showing significant knockdown of at the mRNA and protein levels. Furthermore, with prolonged KD of , ∼40% of mice re-established disease while maintaining KD of the fusion gene. Our work indicates that is required by leukemia cells in the spleen and blood, but that cells in the bone marrow can survive and re-establish disease independent of the fusion protein.