The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

Abstract

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

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Affiliated Institutions

• Seattle Children's Hospital US
• Children's Hospital Colorado US
• University of Virginia US
• University of Padua IT
• University of New Mexico US
• VIB-KU Leuven Center for Cancer Biology BE
• Ontario Institute for Cancer Research CA
• University Health Network CA
• Florida College US
• University of Colorado Denver US
• University of Florida US
• St. Jude Children's Research Hospital US
• University of California, San Francisco US
• Washington University in St. Louis US
• Center for Cancer and Blood Disorders US

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