Unfolding the Role of Calreticulin in Myeloproliferative Neoplasm Pathogenesis.

Abstract

In 2013, two seminal studies identified gain-of-function mutations in the Calreticulin (<i>CALR</i>) gene in a subset of <i>JAK2</i>/<i>MPL</i>-negative myeloproliferative neoplasm (MPN) patients. CALR is an endoplasmic reticulum (ER) chaperone protein that normally binds misfolded proteins in the ER and prevents their export to the Golgi and had never previously been reported mutated in cancer or to be associated with hematologic disorders. Further investigation determined that mutated <i>CALR</i> is able to achieve oncogenic transformation primarily through constitutive activation of the MPL-JAK-STAT signaling axis. Here we review our current understanding of the role of <i>CALR</i> mutations in MPN pathogenesis and how these insights can lead to innovative therapeutics approaches.