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. 2019 Dec 19;134(25):2242-2248.
doi: 10.1182/blood.2019000622.

Mutant calreticulin in myeloproliferative neoplasms

Joan How  1   2   3 , Gabriela S Hobbs  3 , Ann Mullally  1   2   4
Affiliations

Mutant calreticulin in myeloproliferative neoplasms

Joan How et al. Blood. .

Abstract

Recurrent mutations in calreticulin are present in ∼20% of patients with myeloproliferative neoplasms (MPNs). Since its discovery in 2013, we now have a more precise understanding of how mutant CALR, an endoplasmic reticulum chaperone protein, activates the JAK/STAT signaling pathway via a pathogenic binding interaction with the thrombopoietin receptor MPL to induce MPNs. In this Spotlight article, we review the current understanding of the biology underpinning mutant CALR-driven MPNs, discuss clinical implications, and highlight future therapeutic approaches.

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Conflict of interest statement

Conflict-of-interest disclosure: A.M. has received honoraria from Blueprint Medicines, Roche, and Incyte for invited lectures, has served on an advisory board for CTI BioPharma, and receives research support from Janssen Pharmaceuticals. G.S.H. has served on advisory boards for Agios, Celgene, Incyte, and Jazz Pharmaceuticals and has received research support from Bayer, Incyte, and Merck. J.H. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Mechanism of mutant CALR-induced MPN and approaches for therapeutic targeting. (A) A pathogenic binding interaction between MPL and mutant CALR leads to activated MPL-JAK/STAT signaling. 1. Mutant CALR traffics through the ER to bind to immature MPL. 2. Stabilized mutant calreticulin-MPL complex traffics to the cell surface. 3. Mutant CALR induces MPL-JAK/STAT signaling pathway activation. (B) Potential nodes for therapeutic intervention in mutant-CALR–driven MPN. (C) Strategies to induce T-cell–directed immune therapy against mutant-CALR–driven MPN. APC, antigen-presenting cell; MPL, major histocompatibility complex; TCR, T-cell receptor.
See this image and copyright information in PMC

References

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