Genomic subtyping and therapeutic targeting of acute erythroleukemia

被引:109
作者
Iacobucci, Ilaria [1 ]
Wen, Ji [1 ]
Meggendorfer, Manja [2 ]
Choi, John K. [1 ]
Shi, Lei [3 ]
Pounds, Stanley B. [3 ]
Carmichael, Catherine L. [4 ]
Masih, Katherine E. [1 ]
Morris, Sarah M. [1 ]
Lindsley, R. Coleman [5 ]
Janke, Laura J. [1 ]
Alexander, Thomas B. [6 ]
Song, Guangchun [1 ]
Qu, Chunxu [1 ]
Li, Yongjin [7 ]
Payne-Turner, Debbie [1 ]
Tomizawa, Daisuke [8 ]
Kiyokawa, Nobutaka [9 ]
Valentine, Marcus [10 ]
Valentine, Virginia [10 ]
Basso, Giuseppe [11 ,12 ]
Locatelli, Franco [13 ,14 ]
Enemark, Eric J. [15 ]
Kham, Shirley K. Y. [16 ]
Yeoh, Allen E. J. [16 ,17 ]
Ma, Xiaotu [7 ]
Zhou, Xin [7 ]
Sioson, Edgar [7 ]
Rusch, Michael [7 ]
Ries, Rhonda E. [18 ]
Stieglitz, Elliot [19 ,20 ]
Hunger, Stephen P. [21 ,22 ,23 ]
Wei, Andrew H. [4 ,24 ,25 ]
To, L. Bik [26 ,27 ,28 ]
Lewis, Ian D. [28 ]
D'Andrea, Richard J. [29 ,30 ]
Kile, Benjamin T. [31 ,32 ]
Brown, Anna L. [29 ,30 ,33 ]
Scott, Hamish S. [29 ,30 ,33 ]
Hahn, Christopher N. [29 ,30 ,33 ]
Marlton, Paula [34 ,35 ]
Pei, Deqing [3 ]
Cheng, Cheng [3 ]
Loh, Mignon L. [19 ,20 ]
Ebert, Benjamin L. [5 ]
Meshinchi, Soheil [18 ]
Haferlach, Torsten [2 ]
Mullighan, Charles G. [1 ]
机构
[1] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA
[2] MLL Munich Leukemia Lab, Munich, Germany
[3] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA
[4] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic, Australia
[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[6] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA
[7] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA
[8] Natl Ctr Child Hlth & Dev, Childrens Canc Ctr, Div Leukemia & Lymphoma, Tokyo, Japan
[9] Natl Res Inst Child Hlth & Dev, Dept Pediat Hematol & Oncol Res, Tokyo, Japan
[10] St Jude Childrens Res Hosp, Cytogenet Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA
[11] Univ Padua, Dept Childrens & Womens Hlth, Clin Paediat Haematol & Oncol, Padua, Italy
[12] Italian Inst Genom Med, Turin, Italy
[13] Sapienza Univ Rome, Dept Gynecol Obstet & Pediat, Rome, Italy
[14] IRCCS Osped Pediat Bambino Gesu, Dept Pediat Hematol & Oncol, Rome, Italy
[15] St Jude Childrens Res Hosp, Dept Struct Biol, 332 N Lauderdale St, Memphis, TN 38105 USA
[16] Natl Univ Singapore, Ctr Translat Res Acute Leukaemia, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore
[17] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore
[18] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA
[19] Univ Calif San Francisco, Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94143 USA
[20] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA
[21] Univ Penn, Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA
[22] Univ Penn, Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA
[23] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA
[24] Alfred Hosp, Dept Clin Haematol, Melbourne, Vic, Australia
[25] Alfred Hosp, Dept Pathol, Melbourne, Vic, Australia
[26] SA Pathology, Dept Haematol, Adelaide, SA, Australia
[27] Royal Adelaide Hosp, Adelaide, SA, Australia
[28] Univ Adelaide, Fac Hlth Sci, Adelaide, SA, Australia
[29] Univ South Australia, Ctr Canc Biol, Adelaide, SA, Australia
[30] SA Pathology, Adelaide, SA, Australia
[31] Walter & Eliza Hall Inst Med Res, Parkville, Vic, Australia
[32] Monash Univ, Monash Biomed Discovery Inst, Dept Anat & Dev Biol, Melbourne, Vic, Australia
[33] SA Pathology, Dept Genet & Mol Pathol, Adelaide, SA, Australia
[34] Princess Alexandra Hosp, Brisbane, Qld, Australia
[35] Univ Queensland, Sch Clin Med, Brisbane, Qld, Australia
基金
英国医学研究理事会;
关键词
ACUTE MYELOID-LEUKEMIA; ACUTE ERYTHROID LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; WORLD-HEALTH-ORGANIZATION; MYELODYSPLASTIC SYNDROME; CLONAL HEMATOPOIESIS; CRYSTAL-STRUCTURES; CELL-LINE; GENE; MUTATIONS;
D O I
10.1038/s41588-019-0375-1
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.
引用
收藏
页码:694 / +
页数:16
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