Ikaros mutation confers integrin-dependent pre-B cell survival and progression to acute lymphoblastic leukemia
Van Etten, Richard A.
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CitationJoshi, 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.
AbstractDeletion 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820763
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