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.
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Yongjin
authors: Y
authors: Li
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kathryn G
authors: KG
authors: Roberts
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Stephanie M
authors: SM
authors: Dobson
authors: Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
authors: Jaeseung C
authors: JC
authors: Kim
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Debbie
authors: D
authors: Payne-Turner
authors: University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87106, USA.
authors: Richard C
authors: RC
authors: Harvey
authors: Cytogenetics Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Marcus
authors: M
authors: Valentine
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Kelly
authors: K
authors: McCastlain
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: John
authors: J
authors: Easton
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Donald
authors: D
authors: Yergeau
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Laura J
authors: LJ
authors: Janke
authors: 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.
authors: Ying
authors: Y
authors: Shao
authors: University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87106, USA.
authors: I-Ming L
authors: IM
authors: Chen
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Michael
authors: M
authors: Rusch
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: Sasan
authors: S
authors: Zandi
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Steven M
authors: SM
authors: Kornblau
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Marina
authors: M
authors: Konopleva
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Elias
authors: E
authors: Jabbour
authors: Montefiore Medical Center, Bronx, NY 10467, USA.
authors: Elisabeth M
authors: EM
authors: Paietta
authors: Department of Hematology, Shaare Zedek Medicak Center, Jerusalem 910310, Israel.
authors: Jacob M
authors: JM
authors: Rowe
authors: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Ching-Hon
authors: CH
authors: Pui
authors: The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors: Julie
authors: J
authors: Gastier-Foster
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Zhaohui
authors: Z
authors: Gu
authors: The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors: Shalini
authors: S
authors: Reshmi
authors: Department of Pediatrics and the Helen Diller Family Cancer Center, University of California, San Francisco, CA 94115, USA.
authors: Mignon L
authors: ML
authors: Loh
authors: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Janis
authors: J
authors: Racevskis
authors: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Martin S
authors: MS
authors: Tallman
authors: Cancer Research Foundation of New York, Bronx, NY 10514, USA.
authors: Peter H
authors: PH
authors: Wiernik
authors: Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
authors: Mark R
authors: MR
authors: Litzow
authors: University of New Mexico Cancer Research and Treatment Center, Albuquerque, NM 87106, USA.
authors: Cheryl L
authors: CL
authors: Willman
authors: Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817, USA.
authors: John D
authors: JD
authors: McPherson
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: James R
authors: JR
authors: Downing
authors: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: Jinghui
authors: J
authors: Zhang
authors: Princess Margaret Cancer Centre, University Health Network and Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors: John E
authors: JE
authors: Dick
authors: Department of Pediatrics and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors: Stephen P
authors: SP
authors: Hunger
authors: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: charles.mullighan@stjude.org.
authors: Charles G
authors: CG
authors: Mullighan
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001483:Base Sequence; D023061:Gene Order; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D017467:Receptors, Erythropoietin / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D017467:Receptors, Erythropoietin