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Cited by 293Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchPlatelet Disorders and Treatments

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

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Elf, Shannon, Abdelfattah, Nouran S., Chen, Edwin, Perales-Patón, Javier, Rosen, Emily A., Ko, Amy, Peisker, Fabian, Florescu, Natalie +8 more·2016·Cancer Discovery
DOI 10.1158/2159-8290.cd-15-1434PMC PMC4851866

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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. 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. Cancer Discov; 6(4); 368–81. ©2016 AACR. See related commentary by Stanley and Steidl, p. 344. This article is highlighted in the In This Issue feature, p. 331

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    “As nuclear hashing is known to be noisy 89 the nuclear hashing data was used in combination with cell clustering data, as the cells cluster based on treatment status.”

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Authors
Elf, S., Abdelfattah, N. S., Chen, E., Perales-Patón, J., Rosen, E. A., Ko, A., Peisker, F., Florescu, N., Giannini, S., Wolach, O., Morgan, E. A., Tothova, Z., Losman, J.-A., Schneider, R. K., Al-Shahrour, F., & Mullally, A.
Affiliations
  • Brigham and Women's Hospital (US)
  • Spanish National Cancer Research Centre (ES)
  • 1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Broad Institute (US)
  • 2Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Corresponding author
Mullally, Ann
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2016-04-01
Volume
6
Issue
4
Pages
368-381
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-15-1434
PMC
PMC4851866
OpenAlex
W2306779733
Cited by
293
References
2
Citations by year
2026: 21 · 2025: 17 · 2024: 26 · 2023: 20 · 2022: 24 · 2021: 44 · 2020: 34 · 2019: 33 · 2018: 22 · 2017: 31 · 2016: 21
FWCI
25.88
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (K08 HL109734)
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
calreticulin, CALR mutation, myeloproliferative neoplasms, thrombopoietin receptor, MPL, oncogenic transformation, JAK/STAT signaling, JAK2 inhibition, protein-protein interaction, hematopoietic transformation, mouse model
MeSH terms
Animals, Base Sequence, Cell Line, Cell Transformation, Neoplastic, Disease Models, Animal, Female, Hematopoietic Stem Cells, Humans, Mutation, Myeloproliferative Disorders, Phenotype, Protein Binding, Signal Transduction, Bone Marrow Transplantation, Frameshift Mutation, Calreticulin, Protein Kinase Inhibitors, STAT Transcription Factors, Mice, Janus Kinases, Receptors, Thrombopoietin, Protein Interaction Domains and Motifs, Structure Collapse

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