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

View/ Open
Author
Jena, Nilamani
Qi, Xiaoqing
Zhang, Jiangwen
Van Etten, Richard A.
Published Version
https://doi.org/10.1038/ni.2821Metadata
Show full item recordCitation
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.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.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#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820763
Collections
- HMS Scholarly Articles [17714]
Contact administrator regarding this item (to report mistakes or request changes)