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

Gayle P Pouliot,James Degar,Chau D Vo,Kristen E Stevenson,Sofie Peirs,David M Weinstock,Pieter Van Vlierberghe,Laura Hinze,Mignon L Loh,Lewis B Silverman,Stephen P Hunger,Chirag Ganesa,Andrew P Weng,Bose Kochupurakkal,Marian H Harris,Alan D D’Andrea,Melissa Burns ,Justine E Roderick ,Björn Menten ,Lisa A Moreau ,Alejandro Gutiérrez

doi:10.1371/journal.pone.0221288

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.

Highlights

The Fanconi pathway functions in the repair of DNA inter-strand crosslinks and stalled replication forks [1]
The identification of a high frequency of pathogenic Fanconi-BRCA mutations implicates this pathway in the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL), a possibility first raised by the spontaneous development of thymic lymphomas in Brca2-deficient mice [17, 18]
While T-cell transformation can occur with biallelic Fanconi-BRCA pathway mutations [17,18,19], the fact that all mutations in human T-ALL appeared to be monoallelic suggests that partially impaired, rather than absent, Fanconi pathway activity may provide optimal fitness during Tcell transformation

Summary

Introduction

The Fanconi pathway functions in the repair of DNA inter-strand crosslinks and stalled replication forks [1]. Stalled replication forks trigger activation of the upstream Fanconi complex (or Fanconi complex 1), which ubiquitinates FANCD2. Biallelic germline mutations of any Fanconi genes including BRCA2 cause Fanconi anemia, a syndrome characterized by developmental anomalies, bone marrow failure, and a predisposition to acute myeloid leukemia and squamous cell carcinomas [1]. Familial adenomatous polyposis accounts for only a small fraction of colorectal cancers in the general population, APC gene mutations are the most common genetic alteration in sporadic colorectal adenocarcinomas [3, 6]. Given that the pathobiology of sporadic cancers is shared with that of genetic cancer predisposition syndromes across numerous tumor types, the paucity of Fanconi-BRCA mutations reported in sporadic human leukemias would appear to be discordant with the high incidence of leukemia in patients with Fanconi anemia [16]

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Conclusion