title: 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.
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.
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Formica
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Colombo
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Shinton
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brill-Dashoff
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Morse Iii
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Li
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Hardy
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D000066673:Cell Self Renewal; D002872:Chromosome Deletion; D025063:Chromosome Disorders; D002882:Chromosomes, Human, Pair 13; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology* / Q000473:pathology; D051379:Mice; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D026801:Synteny
chemical_list: D011947:Receptors, Antigen, B-Cell; D024507:Nonmuscle Myosin Type IIA