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Nat Immunol. 2014 Mar;15(3):294-304. doi: 10.1038/ni.2821. Epub 2014 Feb 9.

Loss of Ikaros DNA-binding function confers integrin-dependent survival on pre-B cells and progression to acute lymphoblastic leukemia.

Author information

1
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
2
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
3
School of Biological Sciences, The University of Hong Kong, Hong Kong.
4
1] Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA. [2] Present address: Chao Family Comprehensive Cancer Center and Division of Hematology/Oncology, University of California, Irvine, Irvine, California, USA.

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.

PMID:
24509510
PMCID:
PMC4494688
DOI:
10.1038/ni.2821
[Indexed for MEDLINE]
Free PMC Article

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