Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein [3]. In healthy cells, it functions as a chaperone and Ca2+ buffer, assisting in correct protein folding within the ER. It also supports Ca2+-dependent processes like adhesion and integrin signaling, and ensures normal antigen presentation on MHC Class I molecules [3].

In myeloproliferative neoplasms (MPN), somatic mutations in CALR are disease-initiating. These mutations lead to aberrant binding of mutant CALR to the thrombopoietin receptor MPL and ligand-independent activation of JAK-STAT signaling [1]. CALR-mutated hematopoietic stem cells and megakaryocyte progenitors show differential upregulation of unfolded proteins, the proteasome, and the ER stress response. Combined pharmacological inhibition of the proteasome and IRE1-XBP1 axis of the ER stress response preferentially targets Calr-mutated cells over wild-type cells in vivo, ameliorating the MPN phenotype [1]. There are mainly two types of CALR mutants, type 1 and type 2, in MPNs, especially in essential thrombocythemia (ET) and primary myelofibrosis (PMF), and they have distinct clinical/prognostic implications [2,4]. For example, in PMF, a favorable outcome might be restricted to type-1 [4]. The disease phenotype of MPN may be altered through CALR mutant burden and mutant type [5].

In conclusion, CALR is crucial for maintaining cellular proteostasis and normal cell functions. In the context of MPNs, studies on CALR-mutated models have provided insights into the pathogenesis of the disease, suggesting potential therapeutic strategies by targeting the unique vulnerabilities associated with CALR mutations [1].