Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL

Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (<i>IKZF1</i>) is a hallmark of BCR-ABL1⁺ precursor B cell acute lymphoblastic leukemia (pre-B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre-B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1⁺ pre-B ALL together with a new model of inducible expression of wild-type Ikaros in <i>IKZF1</i> mutant human BCR-ABL1⁺ pre-B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1⁺ pre-B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, including <i>CTNND1</i> and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage-specific expression of multiple genes through chromatin compaction at its target genes.