論文

査読有り 国際誌
2016年3月10日

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

Blood
  • Marito Araki
  • ,
  • Yinjie Yang
  • ,
  • Nami Masubuchi
  • ,
  • Yumi Hironaka
  • ,
  • Hiraku Takei
  • ,
  • Soji Morishita
  • ,
  • Yoshihisa Mizukami
  • ,
  • Shin Kan
  • ,
  • Shuichi Shirane
  • ,
  • Yoko Edahiro
  • ,
  • Yoshitaka Sunami
  • ,
  • Akimichi Ohsaka
  • ,
  • Norio Komatsu

127
10
開始ページ
1307
終了ページ
16
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1182/blood-2015-09-671172

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.

リンク情報
DOI
https://doi.org/10.1182/blood-2015-09-671172
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26817954

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