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

Jinghui Zhang, Li Ding, Linda Holmfeldt, Gang Wu, Sue L. Heatley, Debbie Payne-Turner, John Easton, Xiang Chen, Jianmin Wang, Michael Rusch, Charles Lu, Shann-Ching Chen, Lei Wei, J. Racquel Collins-Underwood, Jing Ma, Kathryn G. Roberts, Stanley B. Pounds, Anatoly Ulyanov, Jared Becksfort, Pankaj Gupta, Robert Huether, Richard W. Kriwacki, Matthew Parker, Daniel J. McGoldrick, David Zhao, Daniel Alford, Stephen Espy, Kiran Chand Bobba, Guangchun Song, Deqing Pei, Cheng Cheng, Stefan Roberts, Michael I. Barbato, Dario Campana, Elaine Coustan-Smith, Sheila A. Shurtleff, Susana C. Raimondi, Maria Kleppe, Jan Cools, Kristin A. Shimano, Michelle L. Hermiston, Sergei Doulatov, Kolja Eppert, Elisa Laurenti, Faiyaz Notta, John E. Dick, Giuseppe Basso, Stephen P. Hunger, Mignon L. Loh, Meenakshi Devidas, Brent Wood, Stuart Winter, Kimberley P. Dunsmore, Robert S. Fulton, Lucinda L. Fulton, Xin Hong, Christopher C. Harris, David J. Dooling, Kerri Ochoa, Kimberly J. Johnson, John C. Obenauer, William E. Evans, Ching-Hon Pui, Clayton W. Naeve, Timothy J. Ley, Elaine R. Mardis, Richard K. Wilson, James R. Downing () and Charles G. Mullighan ()
Additional contact information
Jinghui Zhang: St Jude Children’s Research Hospital
Li Ding: The Genome Institute at Washington University
Linda Holmfeldt: St Jude Children’s Research Hospital
Gang Wu: St Jude Children’s Research Hospital
Sue L. Heatley: St Jude Children’s Research Hospital
Debbie Payne-Turner: St Jude Children’s Research Hospital
John Easton: Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Xiang Chen: St Jude Children’s Research Hospital
Jianmin Wang: St Jude Children’s Research Hospital
Michael Rusch: St Jude Children’s Research Hospital
Charles Lu: The Genome Institute at Washington University
Shann-Ching Chen: St Jude Children’s Research Hospital
Lei Wei: St Jude Children’s Research Hospital
J. Racquel Collins-Underwood: St Jude Children’s Research Hospital
Jing Ma: St Jude Children’s Research Hospital
Kathryn G. Roberts: St Jude Children’s Research Hospital
Stanley B. Pounds: St Jude Children’s Research Hospital
Anatoly Ulyanov: St Jude Children’s Research Hospital
Jared Becksfort: St Jude Children’s Research Hospital
Pankaj Gupta: St Jude Children’s Research Hospital
Robert Huether: St Jude Children’s Research Hospital
Richard W. Kriwacki: St Jude Children’s Research Hospital
Matthew Parker: Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Daniel J. McGoldrick: St Jude Children’s Research Hospital
David Zhao: St Jude Children’s Research Hospital
Daniel Alford: St Jude Children’s Research Hospital
Stephen Espy: St Jude Children’s Research Hospital
Kiran Chand Bobba: St Jude Children’s Research Hospital
Guangchun Song: St Jude Children’s Research Hospital
Deqing Pei: St Jude Children’s Research Hospital
Cheng Cheng: St Jude Children’s Research Hospital
Stefan Roberts: Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Michael I. Barbato: Pediatric Cancer Genome Project Laboratory, St Jude Children’s Research Hospital
Dario Campana: St Jude Children’s Research Hospital
Elaine Coustan-Smith: St Jude Children’s Research Hospital
Sheila A. Shurtleff: St Jude Children’s Research Hospital
Susana C. Raimondi: St Jude Children’s Research Hospital
Maria Kleppe: Center for Human Genetics, VIB, K.U.Leuven, 3000 Leuven, Belgium
Jan Cools: Center for Human Genetics, VIB, K.U.Leuven, 3000 Leuven, Belgium
Kristin A. Shimano: University of California School of Medicine
Michelle L. Hermiston: University of California School of Medicine
Sergei Doulatov: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
Kolja Eppert: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
Elisa Laurenti: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
Faiyaz Notta: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
John E. Dick: Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
Giuseppe Basso: Onco-Hematology Laboratory, University of Padua
Stephen P. Hunger: Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation and Center for Cancer and Blood Disorders, University of Colorado Denver School of Medicine, Children’s Hospital Colorado
Mignon L. Loh: University of California School of Medicine
Meenakshi Devidas: University of Florida College of Medicine
Brent Wood: Seattle Children’s Hospital
Stuart Winter: University of New Mexico
Kimberley P. Dunsmore: Pediatric Hematology Oncology, University of Virginia
Robert S. Fulton: The Genome Institute at Washington University
Lucinda L. Fulton: The Genome Institute at Washington University
Xin Hong: The Genome Institute at Washington University
Christopher C. Harris: The Genome Institute at Washington University
David J. Dooling: The Genome Institute at Washington University
Kerri Ochoa: The Genome Institute at Washington University
Kimberly J. Johnson: The Genome Institute at Washington University
John C. Obenauer: St Jude Children’s Research Hospital
William E. Evans: St Jude Children’s Research Hospital
Ching-Hon Pui: St Jude Children’s Research Hospital
Clayton W. Naeve: St Jude Children’s Research Hospital
Timothy J. Ley: The Genome Institute at Washington University
Elaine R. Mardis: The Genome Institute at Washington University
Richard K. Wilson: The Genome Institute at Washington University
James R. Downing: St Jude Children’s Research Hospital
Charles G. Mullighan: St Jude Children’s Research Hospital

Nature, 2012, vol. 481, issue 7380, 157-163

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature10725

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