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Chronic lymphocytic leukemia

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 volume 30, pages 1510–1519 (2016)Cite this article

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Abstract

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.

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Acknowledgements

We thank Carlo M. Croce for providing hTCL1 transgenic mice and Y. Nakao for analysis of tumor-bearing mice. Also, we acknowledge several Fox Chase Cancer Center shared facilities for technical support, flow cytometry, DNA sequencing, cell culture, transgenic mouse, laboratory animals and genomics, including J. Pei for CGH. We thank T. Manser and K. Campbell for discussion and comments. This work was supported by the National Institutes of Health (NIH) RO1 CA129330 (KH), R01 AI049335 (KH), RO1 AI026782 (RRH), RC1 CA145445 (RRH and KH), NIH T32 training grant (MJC), and the Fox Chase Cancer Center Blood Cell Development and Cancer Keystone program, and in part by the Intramural Research Program of the NIH, NIAID.

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  1. Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA

    K Hayakawa, A M Formica, M J Colombo, S A Shinton, J Brill-Dashoff, Y-S Li & R R Hardy

  2. Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    H C Morse III

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  1. K Hayakawa
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Correspondence to K Hayakawa.

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Hayakawa, K., Formica, A., Colombo, M. et al. 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 30, 1510–1519 (2016). https://doi.org/10.1038/leu.2016.61

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