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Cancer Cell. 2016 Feb 8;29(2):186-200. doi: 10.1016/j.ccell.2015.12.013.

Truncating Erythropoietin Receptor Rearrangements in Acute Lymphoblastic Leukemia.

Author information

1
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
2
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
4
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
5
University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87106, USA.
6
Cytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Montefiore Medical Center, Bronx, NY 10467, USA.
10
Department of Hematology, Shaare Zedek Medicak Center, Jerusalem 910310, Israel.
11
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
12
The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
13
Department of Pediatrics and the Helen Diller Family Cancer Center, University of California, San Francisco, CA 94115, USA.
14
Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
15
Cancer Research Foundation of New York, Bronx, NY 10514, USA.
16
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
17
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA.
18
Department of Pediatrics and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
19
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: charles.mullighan@stjude.org.

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.

PMID:
26859458
PMCID:
PMC4750652
DOI:
10.1016/j.ccell.2015.12.013
[Indexed for MEDLINE]
Free PMC Article

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