Calreticulin Ins5 and Del52 Mutations Impair Unfolded Protein and Oxidative Stress Responses in Hematopoietic Cells

Somatic mutations of calreticulin (CALR) have been described in approximately 30-40% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven't been fully unraveled. In order to assess whether and how CALR mutations could affect the physiological CALR protein functions in the ER and thus contributing through other mechanisms to the development of MPNs, we decided to study the role of mutated CALR in K562 cells, devoid of MPL expression. To this end, K562 cells stably expressing either wt CALRor the two most common CALR mutated variants CALRdel52 and CALRins5 were generated via retroviral mediated gene transfer.