@article{a2f3394bb5f544c3950ec672b7296bed,
title = "Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia",
abstract = "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. Iacobucci et al. show that recurrent EPOR rearrangements occur exclusively in Ph-like acute lymphoblastic leukemia (ALL), resulting in the expression of C-terminal truncated EPOR mutants that have heightened JAK-STAT signaling in response to erythropoietin and confer sensitivity to JAK-STAT inhibition in cases with these rearrangements.",
author = "Ilaria Iacobucci and Yongjin Li and Roberts, {Kathryn G.} and Dobson, {Stephanie M.} and Kim, {Jaeseung C.} and Debbie Payne-Turner and Harvey, {Richard C.} and Marcus Valentine and Kelly McCastlain and John Easton and Donald Yergeau and Janke, {Laura J.} and Ying Shao and Chen, {I. Ming L.} and Michael Rusch and Sasan Zandi and Kornblau, {Steven M.} and Marina Konopleva and Elias Jabbour and Paietta, {Elisabeth M.} and Rowe, {Jacob M.} and Pui, {Ching Hon} and Julie Gastier-Foster and Zhaohui Gu and Shalini Reshmi and Loh, {Mignon L.} and Janis Racevskis and Tallman, {Martin S.} and Wiernik, {Peter H.} and Litzow, {Mark R.} and Willman, {Cheryl L.} and McPherson, {John D.} and Downing, {James R.} and Jinghui Zhang and Dick, {John E.} and Hunger, {Stephen P.} and Mullighan, {Charles G.}",
note = "Funding Information: This work was supported in part by the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital ; by a Stand Up to Cancer Innovative Research Grant and St Baldrick's Foundation Scholar Award (to C.G.M.); by a St. Baldrick's Consortium Award (to S.P.H.); by a Leukemia and Lymphoma Society Specialized Center of Research grant (to S.P.H. and C.G.M.); by a Lady Tata Memorial Trust Award (to I.I.); by a Leukemia and Lymphoma Society Special Fellow Award and Alex's Lemonade Stand Foundation Young Investigator Awards (to K.G.R.); and by National Cancer Institute Grants CA21765 (St Jude Cancer Center Support Grant), U01 CA157937 (to C.L.W. and S.P.H.), U24 CA114737 , U10 CA180820 (ECOG-ACRIN Operations), and CA180827 (to E.M.P.); U10 CA101140 (The Alliance Leukemia Correlative Science); CA145707 (to C.L.W. and C.G.M.); and grants to the Children's Oncology Group: U10 CA98543 (Chair's grant and supplement to support the COG ALL TARGET project), U10 CA98413 (Statistical Center), and U24 CA114766 (Specimen Banking). We thank the staff of the St Jude Biorepository, the Hartwell Center for Bioinformatics and Biotechnology, the Flow Cytometry and Cell Sorting Core Facility, the Cell and Tissue Imaging Facility, the Animal Resources Center, and the Small Animal Imaging Center of St. Jude Children's Research Hospital. We thank Incyte Corporation for providing ruxolitinib, Drs E. Parganas and Dr J. Ihle for providing Epor −/+ Balb/c mice, and Amgen Inc. for providing the rabbit monoclonal antibody specific to human EpoR A82. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc..",
year = "2016",
month = feb,
day = "8",
doi = "10.1016/j.ccell.2015.12.013",
language = "English (US)",
volume = "29",
pages = "186--200",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}