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Hayakawa K , Formica AM , Brill-Dashoff J , Shinton SA , Ichikawa D , Zhou Y , Morse HC , Hardy RR
Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression
J Exp Med. 2016 Dec;213(13) :3007-3024
PMID: 27899442    PMCID: PMC5154941    URL: https://www.ncbi.nlm.nih.gov/pubmed/27899442
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In mice, generation of autoreactive CD5(+) B cells occurs as a consequence of BCR signaling induced by (self)-ligand exposure from fetal/neonatal B-1 B cell development. A fraction of these cells self-renew and persist as a minor B1 B cell subset throughout life. Here, we show that transfer of early generated B1 B cells from E mu-TCL1 transgenic mice resulted in chronic lymphocytic leukemia (CLL) with a biased repertoire, including stereotyped BCRs. Thus, B1 B cells bearing restricted BCRs can become CLL during aging. Increased anti-thymocyte/Thy-1 autoreactive (ATA) BCR cells in the B1 B cell subset by transgenic expression yielded spontaneous ATA B-CLL/lymphoma incidence, enhanced by TCL1 transgenesis. In contrast, ATA B-CLL did not develop from other B cell subsets, even when the identical ATA BCR was expressed on a Thy-1 low/null background. Thus, both a specific BCR and B1 B cell context were important for CLL progression. Neonatal B1 B cells and their CLL progeny in aged mice continued to express moderately up-regulated c-Myc and down-regulated proapoptotic Bmf, unlike most mature B cells in the adult. Thus, there is a genetic predisposition inherent in B-1 development generating restricted BCRs and self-renewal capacity, with both features contributing to potential for progression to CLL.
Hayakawa, Kyoko Formica, Anthony M. Brill-Dashoff, Joni Shinton, Susan A. Ichikawa, Daiju Zhou, Yan Morse, Herbert C., III Hardy, Richard R. 1540-9538