title: Early generated B1 B cells with restricted BCRs become chronic lymphocytic leukemia with continued c-Myc and low Bmf expression.
abstract: 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 Eμ-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.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111 Kyoko.Hayakawa@fccc.edu.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Formica
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Joni
authors.initials: J
authors.lastname: Brill-Dashoff
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Shinton
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Daiju
authors.initials: D
authors.lastname: Ichikawa
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Hardy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C435486:Bmf protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D011947:Receptors, Antigen, B-Cell