Schematic representation of the molecular pathogenesis of CALR-mutant MPNs based on the findings of the 3 articles of this issue.1-3 (A) TPO-independent activation of the TPO receptor (MPL) by mutant calreticulin in an individual hematopoietic cell. (i) Abnormal physical interaction between mutant calreticulin and TPO receptor within the ER. (ii) MPL coupled with mutant calreticulin is exported on the cell surface through the Golgi apparatus and/or an alternative pathway. (iii) TPO-independent activation of MPL, and in turn dimerization and activation of JAK2. As a chaperone, calreticulin normally assists proper folding of the TPO receptor (MPL) inside the ER. Mutant calreticulin preferentially interacts with MPL, and the mutant-specific domain of the protein is required for this interaction that leads to stable binding. Here, it is assumed that the MPL dimer is already assembled in the ER, but another possibility is that dimerization occurs on the cell surface. It is also uncertain whether both MPL subunits bind mutant calreticulin, or just one of them does; again, both events might take place. The interaction of mutant calreticulin with MPL activates MPL signaling through JAK2. (B) Biological and clinical consequences. (i) Activated MPL-driven clonal expansion of HSCs. (ii) Excessive platelet production by abnormal megakaryocytes: ET. (iii) Bone marrow reticulin formation: progression from ET to myelofibrosis. Most patients with a CALR-mutant MPN have fully clonal hematopoiesis, indicating that the founding mutation drives clonal expansion at the HSC level. Under normal conditions, adult HSCs are TPO-dependent for their survival and maintenance in the osteoblastic niche10,11 ; thus, mutant calreticulin-induced abnormal MPL signaling is likely responsible for clonal expansion of HSCs carrying a CALR mutation. At the hematopoietic precursor level, the only cells in which MPL signaling is effective are megakaryocytes, and therefore MPL-signaling activation leads to overproduction of platelets. Mutant calreticulin-expressing megakaryocytes also contribute to bone marrow fibrosis, and in the long-term this process leads to a transition from ET to myelofibrosis. Professional illustration by Patrick Lane, ScEYEnce Studios.
