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-INF2α treatment. The NGS study performed at the time of the MM diagnosis revealed the HRAS Val14Gly/c.41T〉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-INF2α 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 1α-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.

Mutations in the miR-142 gene are not common in myeloproliferative neoplasms.

Recent data indicate that MIR142 is the most frequently mutated miRNA gene and one of the most frequently mutated noncoding elements in all cancers, with mutations occurring predominantly in blood cancers, especially diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Functional analyses show that the MIR142 alterations have profound consequences for lympho- and myelopoiesis. Furthermore, one of the targets downregulated by miR-142-5p is CD274, which encodes PD-L1 that is elevated in many cancer types, including myeloproliferative neoplasms (MPNs). To extend knowledge about the occurrence of MIR142 mutations, we sequenced the gene in a large panel of MPNs [~ 700 samples, including polycythemia vera, essential thrombocythemia, primary myelofibrosis (PMF), and chronic myeloid leukemia], neoplasm types in which such mutations have never been tested, and in panels of acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL). We identified 3 mutations (one in a PMF sample and two others in one CLL sample), indicating that MIR142 mutations are rare in MPNs. In summary, mutations in MIR142 are rare in MPNs; however, in specific subtypes, such as PMF, their frequency may be comparable to that observed in CLL or AML.