Department of Molecular, Cell and Cancer Biology
Cancer Biology | Hemic and Lymphatic Diseases | Neoplasms
BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.
Mutation, Cloning, Point mutation, Genetic causes of cancer, Haploinsufficiency, Polymerase chain reaction, Dideoxy DNA sequencing, Gene sequencing
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Copyright: © 2019 Pouliot et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
PLoS One. 2019 Nov 13;14(11):e0221288. doi: 10.1371/journal.pone.0221288. eCollection 2019. Link to article on publisher's site
Pouliot GP, Roderick JE, Gutierrez A. (2019). Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia. Open Access Publications by UMass Chan Authors. https://doi.org/10.1371/journal.pone.0221288. Retrieved from https://escholarship.umassmed.edu/oapubs/4072
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This work is licensed under a Creative Commons Attribution 4.0 License.