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Hayakawa K, Formica AM, Colombo MJ, Shinton SA, Brill-Dashoff J, Morse Iii HC, Li YS, Hardy RR
Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells
Leukemia (2016) 30:1510-9.
A common feature of B-cell chronic lymphocytic leukemia (CLL) is chromosomal loss of 13q14, containing the miR15a/16-1 locus controlling B-cell proliferation. However, CLL etiology remains unclear. CLL is an adult leukemia with an incidence that increases with advancing age. A unique feature of CLL is biased B-cell antigen receptor (BCR) usage, autoreactivity with polyreactivity and CD5 expression, all suggest a role for the BCR in driving CLL pathogenesis. Among human CLLs, BCRs autoreactive with non-muscle myosin IIA (AMyIIA) are recurrent. Here we identify an unmutated AMyIIA BCR in mouse, with distinctive CDR3 segments capable of promoting leukemogenesis. B cells with this AMyIIA BCR are generated by BCR-dependent signaling during B-1 fetal/neonatal development with CD5 induction, but not in adults. These early-generated AMyIIA B-1 B cells self-renew, increase during aging and can progress to become monoclonal B-cell lymphocytosis, followed by aggressive CLL in aged mice, often with the loss of a chromosomal region containing the miR15a/16-1 locus of varying length, as in human CLL. Thus, the ability to generate this defined autoreactive BCR by B-1 B cells is a key predisposing step in mice, promoting progression to chronic leukemia.Leukemia advance online publication, 8 April 2016; doi:10.1038/leu.2016.61.
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Publication Date: 2016-03-08.
PMCID: PMC4979312
Last updated on Tuesday, June 05, 2018