Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation

Shannon Elf, Nouran S. Abdelfattah, Edwin Chen, Javier Perales-Patón, Emily A. Rosen, Amy Ko, Fabian Peisker, Natalie Florescu, Silvia Giannini, Ofir Wolach, Elizabeth A. Morgan, Zuzana Tothova, Julie Aurore Losman, Rebekka K. Schneider, Fatima Al-Shahrour, Ann Mullally*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)368-381
Number of pages14
JournalCancer Discovery
Issue number4
StatePublished - Apr 2016
Externally publishedYes


FundersFunder number
National Institutes of HealthK08HL109734
National Heart, Lung, and Blood InstituteT32HL116324


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