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

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

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Title: Ikaros mutation confers integrin-dependent pre-B cell survival and progression to acute lymphoblastic leukemia
Author: Joshi, Ila; Yoshida, Toshimi; Jena, Nilamani; Qi, Xiaoqing; Zhang, Jiangwen; Van Etten, Richard A.; Georgopoulos, Katia

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Citation: Joshi, Ila, Toshimi Yoshida, Nilamani Jena, Xiaoqing Qi, Jiangwen Zhang, Richard A. Van Etten, and Katia Georgopoulos. 2014. “Ikaros mutation confers integrin-dependent pre-B cell survival and progression to acute lymphoblastic leukemia.” Nature immunology 15 (3): 294-304. doi:10.1038/ni.2821. http://dx.doi.org/10.1038/ni.2821.
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Abstract: Deletion of the Ikaros (Ikzf1) 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.
Published Version: doi:10.1038/ni.2821
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494688/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820763
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