1. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia
- Author
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Stephen P. Hunger, Elisa Laurenti, Pankaj Gupta, Linda Holmfeldt, Shann Ching Chen, David Zhao, Cheng Cheng, William E. Evans, Michael Rusch, Daniel Alford, Sheila A. Shurtleff, Faiyaz Notta, Elaine Coustan-Smith, David J. Dooling, Debbie Payne-Turner, John C. Obenauer, Xiang Chen, Jinghui Zhang, Michelle L. Hermiston, Lei Wei, Daniel J. McGoldrick, Mignon L. Loh, Deqing Pei, Charles Lu, Michael I. Barbato, Kathryn G. Roberts, Jing Ma, Kimberley P. Dunsmore, Kolja Eppert, Meenakshi Devidas, Elaine R. Mardis, Kiran Chand Bobba, Gang Wu, Chris Harris, Susan L. Heatley, James R. Downing, Guangchun Song, Sergei Doulatov, Jared Becksfort, Susana C. Raimondi, Richard K. Wilson, Jianmin Wang, Lucinda Fulton, Kerri Ochoa, Brent L. Wood, Xin Hong, Stanley Pounds, Stephen Espy, Matthew Parker, Robert Huether, Giuseppe Basso, Stuart S. Winter, Maria Kleppe, Stefan Roberts, Richard W. Kriwacki, Li Ding, Ching-Hon Pui, Anatoly Ulyanov, Timothy J. Ley, Jan Cools, J. Racquel Collins-Underwood, John E. Dick, Kristin A. Shimano, Dario Campana, Kimberly J. Johnson, Charles G. Mullighan, Robert S. Fulton, Clayton W. Naeve, and John Easton
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Myeloid ,DNA Copy Number Variations ,T-Lymphocytes ,Molecular Sequence Data ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease_cause ,Article ,Translocation, Genetic ,Histones ,hemic and lymphatic diseases ,medicine ,Humans ,Genetic Predisposition to Disease ,Age of Onset ,Child ,EP300 ,Interleukin-7 receptor ,Janus Kinases ,Receptors, Interleukin-7 ,Multidisciplinary ,Genome, Human ,Stem Cells ,Genomics ,Sequence Analysis, DNA ,medicine.disease ,Hematopoiesis ,Leukemia, Myeloid, Acute ,Reelin Protein ,DNM2 ,Haematopoiesis ,Leukemia ,Genes, ras ,medicine.anatomical_structure ,Mutation ,Immunology ,Cancer research ,KRAS ,Signal Transduction - 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.
- Published
- 2012