Central role for ikaros in pre-B cell differentiation and pathogenesis of high-risk B-cell acute lymphoblastic leukemia

Deletion of the DNA-binding domain of the transcription factor IKAROS generates dominant-negative isoforms that interfere with its activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemia (B-ALL). Conditional inactivation of the IKAROS DNA-binding domain in early pre-B cells arrests their differentiation at a stage at which integrin-dependent adhesion to the bone marrow niche augments signaling via MAPKs, proliferation and self-renewal and attenuates pre-BCR signaling and pre-B cell differentiation. Transplantation of polyclonal Ikzf1-mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, whereas the tyrosine kinase BCR-ABL1 cooperates with Ikzf1 mutation to accelerate B-leukemogenesis, demonstrating that loss of IKAROS contributes to multistep B cell leukemogenesis. IKAROS controls this developmental process by regulating super-enhancers with distinct lineage affiliations. Super-enhancers supporting expression of pre-B cell differentiation genes are dependent on IKAROS for an active chromatin configuration, a function not compensated by other master B cell regulators bound at these sites. IKAROS also directly represses transcription factors implicated in growth and self-renewal of stem-epithelial precursors. Upon IKAROS loss, these extra-lineage regulators activate de novo super-enhancers and a gene expression program that imposes epithelial cell properties on pre-B cells. This phenotype, shared with B-ALL, is sustained by a feed-forward loop based on cooperation between extra-lineage and B-cell factors. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against an epithelial-B cell phenotype that underlies the pathogenesis of high-risk B-ALL.