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Chronic myeloproliferative neoplasms

Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm

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Abstract

Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals. Our results demonstrate that activating JAK2 mutants can differentially couple to selective cytokine receptors and change the signaling repertoire, revealing the molecular basis for phenotypic differences elicited by JAK2 (V617F) or mutations in exon 12. On the basis of these findings, receptor-JAK2 interactions could represent new targets of lineage-specific therapeutic approaches against MPN, which may be applicable to other cancers with aberrant JAK-STAT signaling.

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Acknowledgements

We thank Drs Emery Bresnick, Saghi Ghaffari, Peter Michaely, Sandy Schmid, Jim Palis, Kathleen McGrath, Jian Xu, Srdan Verstovsek, Yumin Shen, Siayareh Rambally and Cheryl Lewis for helpful discussions and input. This study was supported by funding from the National Institute of Health (HL089966), Cancer Prevention Research Institute of Texas (CPRIT, RP110090) and the Ladies Leukemia League to LJ-SH, from the National Natural Science Foundation of China (grant no. 81200379) to ZH and a post-doctoral training grant from CPRIT to HY.

Author contributions

HY, YM, ZH, LZ, M-CH and LJ-SH designed and performed research, and analyzed data. SAM analyzed data. HY and LJ-SH wrote the paper.

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Authors and Affiliations

  1. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    H Yao, Y Ma, Z Hong, L Zhao & L J Huang

  2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    S A Monaghan

  3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    M-C Hu

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  1. H Yao
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  2. Y Ma
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  3. Z Hong
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  4. L Zhao
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  7. L J Huang
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Correspondence to L J Huang.

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Yao, H., Ma, Y., Hong, Z. et al. Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia 31, 2122–2131 (2017). https://doi.org/10.1038/leu.2017.1

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