HRAS Mutation Positive Multiple Myeloma in the Type 2 CALR Mutation Positive Essential Thrombocythemia: A Case Report.

Out of BCR-ABL negative myeloproliferative neoplasm (MPNPh-) patients, 3%-14% display a concomitant monoclonal gammopathy of unknown significance (MGUS). In most cases, the diagnosis of plasma cell dyscrasia is either synchronous with that of MPNPh- or occurs later on. We present a 50-year-old patient with type 2 CALR Lys385Asnfs*47 mutation positive essential thrombocythemia (ET) who developed symptomatic multiple myeloma (MM) 13 years after the diagnosis of ET during PEG-INF2 alpha treatment. The NGS study performed at the time of the MM diagnosis revealed the HRAS Val14Gly/c.41T & rang;G mutation and the wild type CALR, JAK2 and MPL gene sequence. In the presented case, the complete molecular remission of ET was achieved after 16 months of PEG-INF2 alpha treatment. The origin of MM cells in MPNPh- patients remains unknown. Published data suggests that type 2 CALRins5 up-regulate the ATF6 chaperone targets in hematopoietic cells and activate the inositol-requiring enzyme 1 alpha-X-box-binding protein 1 pathway of the unfolded protein response (UPR) system to drive malignancy. It cannot be excluded that endoplasmic reticulum stress induced by the increased ATF6 resulted in an abnormal redox homeostasis and proteostasis, which are factors linked to MM. The presented case history and the proposed mechanism of mutant CALR interaction with UPR and/or ATF6 should initiate the discussion about the possible impact of the mutant CALR protein on the function and genomic stability of different types of myeloid cells, including progenitor cells.