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 Jul;30(7):1510-9. doi: 10.1038/leu.2016.61. Epub 2016 Mar 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology
  • Cell Self Renewal
  • Chromosome Deletion*
  • Chromosome Disorders*
  • Chromosomes, Human, Pair 13
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / etiology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Mice
  • Nonmuscle Myosin Type IIA / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Synteny

Substances

  • Receptors, Antigen, B-Cell
  • Nonmuscle Myosin Type IIA

Supplementary concepts

  • 13q deletion syndrome