Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia
Author
Jena, Nilamani
Qi, Xiaoqing
Zhang, Jiangwen
Van Etten, Richard A
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https://doi.org/10.1038/ni.2821Metadata
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Joshi, 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.Abstract
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). 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494688/Terms of Use
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