Joshi, IlaYoshida, ToshimiJena, NilamaniQi, XiaoqingZhang, JiangwenVan Etten, Richard AGeorgopoulos, Katia2017-05-152014Joshi, Ila, Toshimi Yoshida, Nilamani Jena, Xiaoqing Qi, Jiangwen Zhang, Richard A Van Etten, and Katia Georgopoulos. 2014. Loss of Ikaros DNA-Binding Function Confers Integrin-Dependent Survival on Pre-B Cells and Progression to Acute Lymphoblastic Leukemia. Nat Immunol 15, no. 3: 294–304. doi:10.1038/ni.2821.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:32684030Deletion 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). Here we found that conditional inactivation of the Ikaros DNA-binding domain in early pre-B cells arrested their differentiation at a stage at which integrin-dependent adhesion to niches augmented signaling via mitogen-activated protein kinases, proliferation and self-renewal and attenuated signaling via the pre-B cell signaling complex (pre-BCR) and the differentiation of pre-B cells. Transplantation of polyclonal Ikaros-mutant pre-B cells resulted in long-latency oligoclonal pre-B-ALL, which demonstrates that loss of Ikaros contributes to multistep B cell leukemogenesis. Our results explain how normal pre-B cells transit from a highly proliferative and stroma-dependent phase to a stroma-independent phase during which differentiation is enabled, and suggest potential therapeutic strategies for Ikaros-mutant B-ALL.en-USB-2 cellsJournal Article2017-05-1510.1038/ni.2821