title: Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.
abstract: Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN.
  
  
  CONCLUSIONS
  The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nouran S
authors.initials: NS
authors.lastname: Abdelfattah
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin
authors.initials: E
authors.lastname: Chen
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Perales-Patón
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Rosen
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Amy
authors.initials: A
authors.lastname: Ko
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Fabian
authors.initials: F
authors.lastname: Peisker
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Natalie
authors.initials: N
authors.lastname: Florescu
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giannini
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ofir
authors.initials: O
authors.lastname: Wolach
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Morgan
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tothova
authors.affiliation: Broad Institute, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julie-Aurore
authors.initials: JA
authors.lastname: Losman
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Fatima
authors.initials: F
authors.lastname: Al-Shahrour
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. amullally@partners.org.
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
mesh_terms: D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation; D037282:Calreticulin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016368:Frameshift Mutation; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053628:Receptors, Thrombopoietin / Q000235:genetics* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D055883:Structure Collapse
chemical_list: D037282:Calreticulin; D047428:Protein Kinase Inhibitors; D053628:Receptors, Thrombopoietin; D050791:STAT Transcription Factors; D053612:Janus Kinases