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PLoS One. 2019 Nov 13;14(11):e0221288. doi: 10.1371/journal.pone.0221288. eCollection 2019.

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

Author information

1
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
2
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
3
Center for DNA Damage and Repair and Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
4
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
5
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
6
Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America.
7
Division of Oncology and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
8
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
9
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
11
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Abstract

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.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: AztraZeneca provided AZD6738 for in vivo studies. G.P.P. is now employed by AstraZeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have no other competing financial interests to declare.

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