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; Charles G. Mullighan

doi:10.1038/nature10725

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 GuptaRobert 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, Charles G. Mullighan

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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.

Original language	English
Pages (from-to)	157-163
Number of pages	7
Journal	Nature
Volume	481
Issue number	7380
DOIs	https://doi.org/10.1038/nature10725
State	Published - Jan 12 2012

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Zhang, J., Ding, L., Holmfeldt, L., Wu, G., Heatley, S. L., Payne-Turner, D., Easton, J., Chen, X., Wang, J., Rusch, M., Lu, C., Chen, S. C., Wei, L., Collins-Underwood, J. R., Ma, J., Roberts, K. G., Pounds, S. B., Ulyanov, A., Becksfort, J., ... Mullighan, C. G. (2012). The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature, 481(7380), 157-163. https://doi.org/10.1038/nature10725

@article{10074287b29d4292b5dfbcd7baae38c2,

title = "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.",

author = "Jinghui Zhang and Li Ding and Linda Holmfeldt and Gang Wu and Heatley, {Sue L.} and Debbie Payne-Turner and John Easton and Xiang Chen and Jianmin Wang and Michael Rusch and Charles Lu and Chen, {Shann Ching} and Lei Wei and Collins-Underwood, {J. Racquel} and Jing Ma and Roberts, {Kathryn G.} and Pounds, {Stanley B.} and Anatoly Ulyanov and Jared Becksfort and Pankaj Gupta and Robert Huether and Kriwacki, {Richard W.} and Matthew Parker and McGoldrick, {Daniel J.} and David Zhao and Daniel Alford and Stephen Espy and Bobba, {Kiran Chand} and Guangchun Song and Deqing Pei and Cheng Cheng and Stefan Roberts and Barbato, {Michael I.} and Dario Campana and Elaine Coustan-Smith and Shurtleff, {Sheila A.} and Raimondi, {Susana C.} and Maria Kleppe and Jan Cools and Shimano, {Kristin A.} and Hermiston, {Michelle L.} and Sergei Doulatov and Kolja Eppert and Elisa Laurenti and Faiyaz Notta and Dick, {John E.} and Giuseppe Basso and Hunger, {Stephen P.} and Loh, {Mignon L.} and Meenakshi Devidas and Brent Wood and Stuart Winter and Dunsmore, {Kimberley P.} and Fulton, {Robert S.} and Fulton, {Lucinda L.} and Xin Hong and Harris, {Christopher C.} and Dooling, {David J.} and Kerri Ochoa and Johnson, {Kimberly J.} and Obenauer, {John C.} and Evans, {William E.} and Pui, {Ching Hon} and Naeve, {Clayton W.} and Ley, {Timothy J.} and Mardis, {Elaine R.} and Wilson, {Richard K.} and Downing, {James R.} and Mullighan, {Charles G.}",

note = "Funding Information: Acknowledgements We thank the many members of St Jude Children{\textquoteright}s Research Hospital and The Genome Institute and Siteman Cancer Center at Washington University in St Louis for support. We thank H. Mulder for project sample management, M. Stine for assistance with data deposition, B. Pappas and S. Malone for information technology infrastructure, J. Morris, E. Walker, A. Merriman and G. Neale for performing single-nucleotide polymorphism and gene expression microarrays, W. Yang for assistance with analysis of genomicdata, and J. Stokes for artwork. We thank the Tissue Resources Laboratory, the Flow Cytometry and Cell Sorting Core, and the Clinical Applications of Core Technology Laboratories of the Hartwell Center for Bioinformatics and Biotechnology of St Jude Children{\textquoteright}s Research Hospital. We thank S. Kehoe of Beckman Coulter Genomics for assistance with Sanger sequencing. This work was funded by The St Jude Children{\textquoteright}s Research Hospital – Washington University Pediatric Cancer Genome Project,ALSAC of St Jude Children{\textquoteright}s Research Hospital, Cancer Center supportgrantP30 CA021765, NIH U01 GM92666—PAAR4Kids, grants toR.K.W. from Washington University in St Louis and the National Human Genome Research Institute (NHGRI U54 HG003079), grants to the Children{\textquoteright}s Oncology Group (NCI CA98543, CA98413, CA114766), and grants from Alex{\textquoteright}s Lemonade Stand and St. Baldrick{\textquoteright}s Foundation (to M.L.H.). S.L.H. was supported by a Haematology Society of Australasia and New Zealand New Investigator Scholarship. S.P.H. is the Ergen Family Chair in Pediatric Cancer. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick{\textquoteright}s Scholar.",

year = "2012",

month = jan,

day = "12",

doi = "10.1038/nature10725",

language = "English",

volume = "481",

pages = "157--163",

journal = "Nature",

issn = "0028-0836",

number = "7380",

}

Zhang, J, Ding, L, Holmfeldt, L, Wu, G, Heatley, SL, Payne-Turner, D, Easton, J, Chen, X, Wang, J, Rusch, M, Lu, C, Chen, SC, Wei, L, Collins-Underwood, JR, Ma, J, Roberts, KG, Pounds, SB, Ulyanov, A, Becksfort, J, Gupta, P, Huether, R, Kriwacki, RW, Parker, M, McGoldrick, DJ, Zhao, D, Alford, D, Espy, S, Bobba, KC, Song, G, Pei, D, Cheng, C, Roberts, S, Barbato, MI, Campana, D, Coustan-Smith, E, Shurtleff, SA, Raimondi, SC, Kleppe, M, Cools, J, Shimano, KA, Hermiston, ML, Doulatov, S, Eppert, K, Laurenti, E, Notta, F, Dick, JE, Basso, G, Hunger, SP, Loh, ML, Devidas, M, Wood, B, Winter, S, Dunsmore, KP, Fulton, RS , Fulton, LL, Hong, X, Harris, CC, Dooling, DJ, Ochoa, K, Johnson, KJ, Obenauer, JC, Evans, WE, Pui, CH, Naeve, CW, Ley, TJ, Mardis, ER, Wilson, RK, Downing, JR & Mullighan, CG 2012, 'The genetic basis of early T-cell precursor acute lymphoblastic leukaemia', Nature, vol. 481, no. 7380, pp. 157-163. https://doi.org/10.1038/nature10725

TY - JOUR

T1 - The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

AU - Zhang, Jinghui

AU - Ding, Li

AU - Holmfeldt, Linda

AU - Wu, Gang

AU - Heatley, Sue L.

AU - Payne-Turner, Debbie

AU - Easton, John

AU - Chen, Xiang

AU - Wang, Jianmin

AU - Rusch, Michael

AU - Lu, Charles

AU - Chen, Shann Ching

AU - Wei, Lei

AU - Collins-Underwood, J. Racquel

AU - Ma, Jing

AU - Roberts, Kathryn G.

AU - Pounds, Stanley B.

AU - Ulyanov, Anatoly

AU - Becksfort, Jared

AU - Gupta, Pankaj

AU - Huether, Robert

AU - Kriwacki, Richard W.

AU - Parker, Matthew

AU - McGoldrick, Daniel J.

AU - Zhao, David

AU - Alford, Daniel

AU - Espy, Stephen

AU - Bobba, Kiran Chand

AU - Song, Guangchun

AU - Pei, Deqing

AU - Cheng, Cheng

AU - Roberts, Stefan

AU - Barbato, Michael I.

AU - Campana, Dario

AU - Coustan-Smith, Elaine

AU - Shurtleff, Sheila A.

AU - Raimondi, Susana C.

AU - Kleppe, Maria

AU - Cools, Jan

AU - Shimano, Kristin A.

AU - Hermiston, Michelle L.

AU - Doulatov, Sergei

AU - Eppert, Kolja

AU - Laurenti, Elisa

AU - Notta, Faiyaz

AU - Dick, John E.

AU - Basso, Giuseppe

AU - Hunger, Stephen P.

AU - Loh, Mignon L.

AU - Devidas, Meenakshi

AU - Wood, Brent

AU - Winter, Stuart

AU - Dunsmore, Kimberley P.

AU - Fulton, Robert S.

AU - Fulton, Lucinda L.

AU - Hong, Xin

AU - Harris, Christopher C.

AU - Dooling, David J.

AU - Ochoa, Kerri

AU - Johnson, Kimberly J.

AU - Obenauer, John C.

AU - Evans, William E.

AU - Pui, Ching Hon

AU - Naeve, Clayton W.

AU - Ley, Timothy J.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Downing, James R.

AU - Mullighan, Charles G.

N1 - Funding Information: Acknowledgements We thank the many members of St Jude Children’s Research Hospital and The Genome Institute and Siteman Cancer Center at Washington University in St Louis for support. We thank H. Mulder for project sample management, M. Stine for assistance with data deposition, B. Pappas and S. Malone for information technology infrastructure, J. Morris, E. Walker, A. Merriman and G. Neale for performing single-nucleotide polymorphism and gene expression microarrays, W. Yang for assistance with analysis of genomicdata, and J. Stokes for artwork. We thank the Tissue Resources Laboratory, the Flow Cytometry and Cell Sorting Core, and the Clinical Applications of Core Technology Laboratories of the Hartwell Center for Bioinformatics and Biotechnology of St Jude Children’s Research Hospital. We thank S. Kehoe of Beckman Coulter Genomics for assistance with Sanger sequencing. This work was funded by The St Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project,ALSAC of St Jude Children’s Research Hospital, Cancer Center supportgrantP30 CA021765, NIH U01 GM92666—PAAR4Kids, grants toR.K.W. from Washington University in St Louis and the National Human Genome Research Institute (NHGRI U54 HG003079), grants to the Children’s Oncology Group (NCI CA98543, CA98413, CA114766), and grants from Alex’s Lemonade Stand and St. Baldrick’s Foundation (to M.L.H.). S.L.H. was supported by a Haematology Society of Australasia and New Zealand New Investigator Scholarship. S.P.H. is the Ergen Family Chair in Pediatric Cancer. C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick’s Scholar.

PY - 2012/1/12

Y1 - 2012/1/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84862907593&partnerID=8YFLogxK

U2 - 10.1038/nature10725

DO - 10.1038/nature10725

M3 - Article

C2 - 22237106

AN - SCOPUS:84862907593

SN - 0028-0836

VL - 481

SP - 157

EP - 163

JO - Nature

JF - Nature

IS - 7380

ER -

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

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