Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jan 28;15(2):160.
doi: 10.3390/ph15020160.

JAK2 in Myeloproliferative Neoplasms: Still a Protagonist

Michael Stephan Bader  1 , Sara Christina Meyer  1   2
Affiliations
Review

JAK2 in Myeloproliferative Neoplasms: Still a Protagonist

Michael Stephan Bader et al. Pharmaceuticals (Basel). .

Abstract

The discovery of the activating V617F mutation in Janus kinase 2 (JAK2) has been decisive for the understanding of myeloproliferative neoplasms (MPN). Activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN. JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients. However, several key aspects remain unsolved regarding the targeted therapy of MPN with JAK2 inhibitors, such as reducing the MPN clone and how to avoid or overcome a loss of response. Here, we summarize the current knowledge on the structure and signaling of JAK2 as central elements of MPN pathogenesis and feature benefits and limitations of therapeutic JAK2 targeting in MPN.

Keywords: JAK2; JAK2 inhibitors; myeloproliferative neoplasms; resistance.

PubMed Disclaimer

Conflict of interest statement

SCM has consulted for and received honoraria from Celgene/BMS and Novartis. MSB has no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Schematic representation of the JAK2 domain structure. Seven Janus homology domains (JH1–JH7) constitute the N-terminal FERM and SH2 domain associating with the intracellular domains of cell surface receptors as well as the C-terminal pseudokinase and kinase domain of JAK2. The JAK2 V617F mutation locates to the pseudokinase domain, interfering with the basal inhibitory effect of the pseudokinase on the kinase domain, leading to constitutive JAK2 activation.
Figure 2
Figure 2
The JAK-STAT signaling pathway in MPN.
Figure 3
Figure 3
JAK2 signaling also activates MAPK and PI3K/Akt pathways, promoting cell proliferation and survival.
See this image and copyright information in PMC

References

    1. Hammarén H.M., Virtanen A.T., Raivola J., Silvennoinen O. The Regulation of JAKs in Cytokine Signaling and Its Breakdown in Disease. Cytokine. 2019;118:48–63. doi: 10.1016/j.cyto.2018.03.041. - DOI - PubMed
    1. Meyer S.C., Levine R.L. Molecular Pathways: Molecular Basis for Sensitivity and Resistance to JAK Kinase Inhibitors. Clin. Cancer Res. 2014;20:2051–2059. doi: 10.1158/1078-0432.CCR-13-0279. - DOI - PMC - PubMed
    1. Skoda R.C., Duek A., Grisouard J. Pathogenesis of Myeloproliferative Neoplasms. Exp. Hematol. 2015;43:599–608. doi: 10.1016/j.exphem.2015.06.007. - DOI - PubMed
    1. O’Shea J.J., Plenge R. JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease. Immunity. 2012;36:542–550. doi: 10.1016/j.immuni.2012.03.014. - DOI - PMC - PubMed
    1. McNally R., Toms A.V., Eck M.J. Crystal Structure of the FERM-SH2 Module of Human Jak2. PLoS ONE. 2016;11:e0156218. doi: 10.1371/journal.pone.0156218. - DOI - PMC - PubMed