Role of Ikzf3 as a Driver Mutation in B Cell Acute Lymphoblastic Leukemia
Abstract
B cell acute lymphoblastic leukemia (B-ALL) involves the cooperation between primary and secondary mutations. Using the Mb1-CreΔPB mouse model, we previously showed that PU.1 and Spi-B deletion leads to B-ALL. Whole-exome sequencing of leukemias revealed secondary mutations in the transcription factor Ikzf3. H195Y, corresponding to H196Y in humans, occurs within the DNA binding domain. We hypothesized that expression of H195/6Y IKZF3 alters gene expression in precursor B cells. RT-qPCR revealed H195/6Y Ikzf3-transduced cells had increased expression of Igll1, which encodes λ5—a component of the pre-B cell receptor. Interactions between IKZF3 and Igll1 were measured by co-transfecting cells with wild-type or H195/6Y Ikzf3 and the Igll1 promoter fused to firefly luciferase. H195/6Y Ikzf3-transfected cells had increased Igll1-driven expression of firefly luciferase, and mutating IKZF3 binding sites within the Igll1 promoter abolished this effect. Collectively, these results suggest that H195/6Y IKZF3 has altered activity and transcriptionally activates Igll1 through direct interactions.