Ikaros mutation confers integrin-dependent pre-B cell survival and progression to acute lymphoblastic leukemia

Deletion of the Ikaros DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL).  Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL.   Overall design: One of the analyses described in this manuscript is the differential gene expression of large preB cells sorted from the bone marrow of WT and IKDN mice. The RNASeq method and Deseq analysis algorithm were employed

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Joshi I, Yoshida T, Jena N, Qi X, Zhang J, Van Etten RA, Georgopoulos K