The JAK2V617F mutation was identified in 2005. Although our knowledge of the exact role of JAK2V617F in the pathogenesis of MPN is far from complete, much information has been gained in the eight years since its discovery and has led to the FDA approval of the JAK1/2 inhibitor ruxolitinib for the treatment of myelofibrosis. The presence of calreticulin mutations in MPN was first reported in December 2013, virtually nothing is known about the mechanism by which calreticulin mutations drive the pathogenesis of MPN.

The recent identification of calreticulin mutations in JAK2V617F-negative patients aligns nicely with our current working model of inflammation as a driver of clonal expansion in MPN. Calreticulin is an “eat me” signal on stressed cells allowing for their “clean and quick” phagocytosis by macrophages. Upregulation of CD47, the “don’t eat me signal” is a common feature of many leukemias and solid tumors that allows them to evade phagocytosis. We hypothesize that the MPN associated calreticulin mutations allow mutant hematopoietic stem cells to evade phagocytosis. Protection from phagocytosis would give these mutant hematopoietic stem cells a competitive advantage over their normal counterparts. The retention of dead and dying cells would result in an inflammatory response, providing an explanation for the excessive inflammation seen in MPN.

Calreticulin has distinct functions depending on its cellular localization. In the ER it serves as a chaperone and binds to misfolded proteins, preventing them from being exported to the Golgi apparatus.  At the cell surface, calreticulin facilitates uptake by macrophages. Induction of cell surface calreticulin is seen in pre-apoptotic, apoptotic, and dying cells as well as cancer cells. Soluble calreticulin is a potent activator of macrophages, contributing to autoimmunity and anti-tumor responses, increased serum calreticulin is seen in autoimmune diseases as well as lung cancer patients.

We are currently working to compare levels of calreticulin in MPN patients versus normal controls. We are also working to compare the sensitivity of MPN versus normal cells to phagocytosis by macrophages.

Identification of abnormalities in the phagocytic axis in MPN patients would reveal a novel therapeutic target for MPN. For example, if the mutant hematopoietic stem and progenitor are resistant to phagocytosis then we would develop methods for making them more vulnerable to phagocytosis. Therapeutics are currently in development to neutralize CD47 “don’t eat me signal” demonstrating the targeting the phagocytic axis is clinically feasible.