Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia

被引：114

作者：

Iacobucci, Ilaria ^{[1
]}

Li, Yongjin ^{[2
]}

Roberts, Kathryn G. ^{[1
]}

Dobson, Stephanie M. ^{[3
,4
]}

Kim, Jaeseung C. ^{[5
,6
]}

Payne-Turner, Debbie ^{[1
]}

Harvey, Richard C. ^{[7
]}

Valentine, Marcus ^{[8
]}

McCastlain, Kelly ^{[1
]}

Easton, John ^{[2
]}

Yergeau, Donald ^{[2
]}

Janke, Laura J. ^{[1
]}

Shao, Ying ^{[1
,2
]}

Chen, I-Ming L. ^{[7
]}

Rusch, Michael ^{[2
]}

Zandi, Sasan ^{[3
,4
]}

Kornblau, Steven M. ^{[9
]}

Konopleva, Marina ^{[9
]}

Jabbour, Elias ^{[9
]}

Paietta, Elisabeth M. ^{[10
]}

Rowe, Jacob M. ^{[11
]}

Pui, Ching-Hon ^{[12
]}

Gastier-Foster, Julie ^{[13
]}

Gu, Zhaohui ^{[1
]}

Reshmi, Shalini ^{[13
]}

Loh, Mignon L. ^{[14
,15
]}

Racevskis, Janis ^{[9
]}

Tallman, Martin S. ^{[16
]}

Wiernik, Peter H. ^{[17
]}

Litzow, Mark R. ^{[18
]}

Willman, Cheryl L. ^{[7
]}

McPherson, John D. ^{[19
]}

Downing, James R. ^{[1
]}

Zhang, Jinghui ^{[2
]}

Dick, John E. ^{[3
,4
]}

Hunger, Stephen P. ^{[20
,21
]}

Mullighan, Charles G. ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[3] Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[4] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada

[5] Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[6] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[7] Univ New Mexico, Canc Res & Treatment Ctr, Albuquerque, NM 87106 USA

[8] St Jude Childrens Res Hosp, Cytogenet Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA

[9] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[10] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA

[11] Shaare Zedek Med Ctr, Dept Hematol, IL-910310 Jerusalem, Israel

[12] St Jude Childrens Res Hosp, Dept Oncol, 332 N Lauderdale St, Memphis, TN 38105 USA

[13] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA

[14] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94115 USA

[15] Univ Calif San Francisco, Helen Diller Family Canc Ctr, San Francisco, CA 94115 USA

[16] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10065 USA

[17] Canc Res Fdn New York, Bronx, NY 10514 USA

[18] Mayo Clin, Div Hematol, Rochester, MN 55905 USA

[19] UC Davis Comprehens Canc Ctr, Dept Biochem & Mol Med, Sacramento, CA 95817 USA

[20] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA

[21] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

来源：

CANCER CELL | 2016年 / 29卷 / 02期

关键词：

KINASE INHIBITOR THERAPY; OF-FUNCTION MUTATIONS; HIGH-RISK; GENETIC ALTERATIONS; PROGENITOR; RECOMBINATION; EXPRESSION; MECHANISM; DELETION; LACKING;

D O I：

10.1016/j.ccell.2015.12.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.

引用

页码：186 / 200

页数：15

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