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Editorial
. 2022 Sep 15;140(11):1187-1189.
doi: 10.1182/blood.2022017448.

Mutant CALR's "sweet tooth"

Sridhar Rao  1   2 , Karen Carlson  1   2
Affiliations
Editorial

Mutant CALR's "sweet tooth"

Sridhar Rao et al. Blood. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
The thrombopoietin receptor (MPL, maroon) requires N-linked glycosylation (blue) via a multistep enzymatic process in the endoplasmic reticulum and association with calreticulin (orange) to be translocated to the cell surface. CALR binding to glycosylated MPL in the cytoplasm facilitates transport to the cell surface. Mutant CALR (red) induces constitutive MPL signaling to confer cytokine-independent proliferation to hematopoietic cells, the ultimate cause of MPNs. Although the mutant CALR was known to require N-glycosylation, dependent on the enzyme DPM2 for its association with MPL, whether this was potentially targetable was unknown. Genetic loss of DPM2 or inhibition of N-glycosylation with small molecules, including 2-DG, reduced cell surface expression of MPL and decreased MPL activity as measured by STAT activation. Collectively, this indicates that targeting N-glycosylation is a potential therapeutic vulnerability in MPNs. Please note that CALR binds to MPL likely in both the cytoplasm and extracellular space. Professional illustration by Somersault18:24.
See this image and copyright information in PMC

Comment on

References

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