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. 2016 Mar 10;127(10):1307-16.
doi: 10.1182/blood-2015-09-671172. Epub 2016 Jan 27.

Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms

Marito Araki  1 , Yinjie Yang  2 , Nami Masubuchi  3 , Yumi Hironaka  2 , Hiraku Takei  2 , Soji Morishita  1 , Yoshihisa Mizukami  4 , Shin Kan  5 , Shuichi Shirane  2 , Yoko Edahiro  2 , Yoshitaka Sunami  2 , Akimichi Ohsaka  1 , Norio Komatsu  2
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Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms

Marito Araki et al. Blood. .
Free article

Abstract

Recurrent somatic mutations of calreticulin (CALR) have been identified in patients harboring myeloproliferative neoplasms; however, their role in tumorigenesis remains elusive. Here, we found that the expression of mutant but not wild-type CALR induces the thrombopoietin (TPO)-independent growth of UT-7/TPO cells. We demonstrated that c-MPL, the TPO receptor, is required for this cytokine-independent growth of UT-7/TPO cells. Mutant CALR preferentially associates with c-MPL that is bound to Janus kinase 2 (JAK2) over the wild-type protein. Furthermore, we demonstrated that the mutant-specific carboxyl terminus portion of CALR interferes with the P-domain of CALR to allow the N-domain to interact with c-MPL, providing an explanation for the gain-of-function property of mutant CALR. We showed that mutant CALR induces the phosphorylation of JAK2 and its downstream signaling molecules in UT-7/TPO cells and that this induction was blocked by JAK2 inhibitor treatment. Finally, we demonstrated that c-MPL is required for TPO-independent megakaryopoiesis in induced pluripotent stem cell-derived hematopoietic stem cells harboring the CALR mutation. These findings imply that mutant CALR activates the JAK2 downstream pathway via its association with c-MPL. Considering these results, we propose that mutant CALR promotes myeloproliferative neoplasm development by activating c-MPL and its downstream pathway.

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