Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations

Tatiana V Makarik,Andrey B Sudarikov,Sergei M Kulikov,Irina N Subortseva,Elena E Nikulina,Anait L Melikyan,Svetlana A Treglazova,Adhamjon O Abdullaev,Alla M Kovrigina,Elena E Stepanova

doi:10.3390/genes12040559

Tatiana V Makarik, Andrey B Sudarikov + Show 8 more

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https://doi.org/10.3390/genes12040559

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Abstract

JAK2 (Janus kinase 2) V617F, CALR (Calreticulin) exon 9, and MPL (receptor for thrombopoietin) exon 10 mutations are associated with the vast majority of Ph-negative chronic myeloproliferative neoplasms (MPNs). These mutations affect sequential stages of proliferative signal transduction and therefore, after the emergence of one type of mutation, other types should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Our study includes DNA samples from 1958 patients with clinical evidence of MPN, admitted to the National Research Center for Hematology for genetic analysis between 2016 and 2019. In 315 of 1402 cases (22.6%), CALR mutations were detected. In 23 of these 315 cases (7.3%), the JAK2 V617F mutation was found in addition to the CALR mutation. In 16 from 24 (69.6%) cases, with combined CALR and JAK2 mutations, V617F allele burden was lower than 1%. A combination of JAK2 V617F with MPL W515L/K was also observed in 1 out of 1348 cases, only. JAK2 allele burden in this case was also lower than 1%. Additional mutations may coexist over the low background of JAK2 V617F allele. Therefore, in cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR. The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.

Highlights

Ph-negative myeloproliferative neoplasms (MPNs) arise as a result of the transformation of the hematopoietic stem cell, which leads to the aberrant clonal hematopoiesis and hyperplasia of the cells of the myeloid lineage [1]
The beginning of deciphering these mechanisms started with the identification of the pathogenetic role of the chimeric BCR/ABL oncogene in chronic myeloid leukemia (CML), which arises as a result of reciprocal t(9:22) translocation forming the so-called Philadelphia chromosome [2,3]
A combined group of patients (1958) with diagnoses of essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), and MPN-U was examined for the presence of JAK2 V617F, JAK2 exon 12, MPL W515L/K, and calreticulin gene (CALR) exon 9 gene mutations

Summary

Introduction

Ph-negative myeloproliferative neoplasms (MPNs) arise as a result of the transformation of the hematopoietic stem cell, which leads to the aberrant clonal hematopoiesis and hyperplasia of the cells of the myeloid lineage [1]. The WHO (World Health Organization) classification of myeloid malignancies includes the following MPNs: Chronic myeloid leukemia (CML), chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia, and others, unclassified MPNs-U. These diseases are characterized by the hyperplasia of the myeloid cell lineages, thrombocytosis, splenomegaly, frequent thrombotic complications, with a long course—the risk of transformation to myelodysplastic syndrome and acute leukemia. The abnormal tyrosine kinase activity of the BCR/ABL protein leads to the dysregulation of many intracellular signaling pathways [4,5]

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