Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation

Cancer Discov. 2016 Apr;6(4):368-81. doi: 10.1158/2159-8290.CD-15-1434. Epub 2016 Mar 7.


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.

Significance: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow Transplantation
  • Calreticulin / chemistry
  • Calreticulin / genetics*
  • Calreticulin / metabolism
  • Cell Line
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Disease Models, Animal
  • Female
  • Frameshift Mutation
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Mice
  • Mutation*
  • Myeloproliferative Disorders / genetics
  • Myeloproliferative Disorders / metabolism
  • Myeloproliferative Disorders / pathology
  • Phenotype
  • Protein Binding
  • Protein Interaction Domains and Motifs / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Thrombopoietin / genetics*
  • Receptors, Thrombopoietin / metabolism
  • STAT Transcription Factors / metabolism
  • Signal Transduction
  • Structure Collapse


  • Calreticulin
  • Protein Kinase Inhibitors
  • Receptors, Thrombopoietin
  • STAT Transcription Factors
  • Janus Kinases