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Chronic myeloproliferative neoplasms

AKT activation is a feature of CALR mutant myeloproliferative neoplasms

Leukemia volume 33, pages 271–274 (2019)Cite this article

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Among the driver mutations in the MPNs, the mechanism by which CALR mutations activate JAK/STAT signaling is unique in that the novel C-terminus of CALR mutant proteins binds directly to MPL leading to constitutive activation [1, 2]. CALR mutants have also been shown to activate the MAPK pathway [3]. Whether CALR mutants further activate PI3K/AKT signaling is controversial, with several studies reporting a lack of (or modest) activation [2, 4], but another demonstrating potent activation [5]. The former studies relied upon transduction of Ba/F3 TpoR cells with CALR mutant alleles whereas the latter probed the pathway in cells lines with megakaryocytic potential. Moreover, the extent to which PI3K/AKT signaling is a target in CALR mutant MPNs has been debated, with at least one study reporting that inhibitors of this pathway do not synergize with ruxolitinib [2].

We previously reported that inhibition of AKT activity with the selective AKT inhibitor MK-2206 resulted in reduced growth of MPLW515L expressing cells both in vitro and in vivo, suggesting that this pathway is a therapeutic target in ET and PMF [6]. To determine whether CALR mutant expressing cells are similarly dependent on PI3K/AKT signaling, we treated CD34+ cells from PMF patients or healthy individuals with MK-2206. We found that CALR mutant cells were susceptible to AKT inhibition and more sensitive than healthy progenitor cells in colony assays (Figs. 1e, f). Of note, the differential effect was much more significant for megakaryocyte colonies (Fig. 1f) than for myeloid colonies (Fig. 1e), consistent with a reliance of megakaryocytes on MPL signaling. Finally, while the level of p-AKT was higher in bone marrow cells from mice transplanted with CALRdel52 expressing cells compared to those with empty vector, the degree of inhibition was similar (Fig. 1g).

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Fig. 1
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Acknowledgements

The authors thank Zan Huang for the CALR mutant expressing plasmids. This study was supported by NIH grant HL112792.

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Authors and Affiliations

  1. Blood Disease Institute, Xuzhou Medical University, Xuzhou, China

    Chunling Fu, Wei Chen & Kailin Xu

  2. Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA

    Chunling Fu, Qiang Jeremy Wen, Christian Marinaccio, Te Ling, Wei Chen, Marinka Bulic & John D. Crispino

  3. Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

    Terra Lasho & Ayalew Tefferi

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  1. Chunling Fu
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Correspondence to John D. Crispino or Kailin Xu.

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Fu, C., Wen, Q.J., Marinaccio, C. et al. AKT activation is a feature of CALR mutant myeloproliferative neoplasms. Leukemia 33, 271–274 (2019). https://doi.org/10.1038/s41375-018-0224-8

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