Journal
PLOS ONE
Volume 14, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0221288
Keywords
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Categories
Funding
- NIH [R01 CA193651]
- Boston Children's Hospital Translational Research Program
- William Lawrence and Blanche Hughes Foundation
- COG Chair's grant [U10 CA98543]
- COG Statistical Center [U10 CA98413]
- COG Specimen Banking [U24 CA114766]
- COG Operations Center [U10 CA180886]
- COG Statistics and Data Center [U10 CA180899]
- Research Foundation Flanders (FWO)
- Ghent University Special Research Fund (BOF)
- Flemish cancer society Stand Up To Cancer (KOTK)
- Boston Children's Hospital
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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.
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