Genomic Instability Resulting from Blm Deficiency Compromises Development, Maintenance, and Function of the B Cell Lineage

Abstract

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.

Human RecQ Helicases in DNA Repair, Recombination, and Replication

“…When 53BP1-defective human cells were treated with a small-molecule WRN inhibitor or a hypomorphic Blm allele ( Blm 3/3 ) was expressed, an I-SceI intrachromosomal break was repaired normally by Alt-NHEJ, but the efficiency of B cell class-switch recombination, which requires Alt-NHEJ, increased (140, 150). To explain these results, the investigators proposed that 53BP1 and phosphorylated histone H2AX (γ-H2AX) compete with proresection enzymes, WRN and BLM, for DSBs and that the circumstances that limit DNA resection in B cells promote Alt-NHEJ and class-switch recombination (140).…”

Bloom's Syndrome: Clinical Spectrum, Molecular Pathogenesis, and Cancer Predisposition

“…Ablation of BLM in the T-cell and B-cell lineages in mice impairs development, maintenance and function of these lineages, supporting the role of BLM in immune integrity [Babbe et al, 2007[Babbe et al, , 2009. In humans, most of the information Kerckhove et al, 1988] and impaired T cell proliferation in vitro [Hütteroth et al, 1975;Van Kerckhove et al, 1988].…”

The role of RecQ helicases in non-homologous end-joining

“…They concluded that BLM and WRN may contribute to the repair of AID-mediated DNA lesions that occur within the repetitive G-rich and highly transcribed switch regions in B lymphocytes, and that minimizing resection favors efficient CSR (Bothmer et al , 2013; Stavnezer et al , 2008). In addition, Babbe and colleagues (2009) showed that BLM-deficient lymphocytes show altered CSR in Iga1, Iga2 and Iga3 genes in splenic B cells, and BLM-deficient B cells have a mild shift towards MMEJ. Additionally, they found that p53-deficient conditional Blm mice showed an increase in propensity for B cell lymphoma development, and that the cells from these mice showed impaired cell cycle progression and survival and high rates of chromosomal structure abnormalities.…”

“…Additionally, they found that p53-deficient conditional Blm mice showed an increase in propensity for B cell lymphoma development, and that the cells from these mice showed impaired cell cycle progression and survival and high rates of chromosomal structure abnormalities. Their data suggests that BLM and p53 cooperate in avoiding lymphoma development and in maintaining chromosomal stability (Babbe et al , 2009). …”