Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage.
The RecQ family helicase BLM is critically involved in the maintenance of genomic stability, and BLM mutation causes the heritable disorder Bloom's syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum Ab titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naive mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG Ab responses upon immunization were poor and mutant B cells exhibited a generally reduced Ab class switch capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift toward microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts were identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.
Babbe
Holger
H
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. hbabbe@genetics.med.harvard.edu
McMenamin
Jennifer
J
Hobeika
Elias
E
Wang
Jing
J
Rodig
Scott J
SJ
Reth
Michael
M
Leder
Philip
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D001816:Bloom Syndrome / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D004261:DNA Replication / Q000235:genetics / Q000276:immunology; D042822:Genomic Instability / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007134:Immunoglobulin Switch Region / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D053484:RecQ Helicases / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011995:Recombination, Genetic / Q000276:immunology
D007132:Immunoglobulin Isotypes; C097151:Bloom syndrome protein; D053484:RecQ Helicases