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Abstract
The identification of JAK2 mutations as disease-initiating in myeloproliferative neoplasms (MPNs) has led to new and effective therapies for these diseases. In a study published in this issue of the JCI, Stivala et al. explored the key observation that JAK inhibition successfully suppresses MAPK activation in MPN cell lines and primary MPN cells in vitro, and the finding that it failed to completely and effectively suppress MAPK activation in vivo in two mouse models. The authors went on to show that dual inhibition of JAK and the MAP kinase pathway provided enhanced therapeutic efficacy in the in vivo models of MPN.
Authors
David A. Williams
Figure 1
Inhibiting the JAK pathway in MPN.
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(A and B ) Ex vivo inhibition strategy. Activation of the JAK pathway leads to enhanced cell proliferation, a hallmark of MPN. JAK2 inhibition ex vivo inhibits MEK/ERK signaling, ultimately leading to a reduction in cell proliferation. (C and D ) In vivo inhibition strategy. JAK2 inhibitors are not able to induce molecular remissions in vivo. JAK2-independent compensatory activation of the MEK/ERK signaling pathway is attributed to activated PDGFR. Combined targeting of JAK2 and MEK inhibits ERK activation and reduces cell proliferation in vivo. MPLR, thrombopoietin receptor. Figure illustrated by Rachel Davidowitz.
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Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)