Analysis of JAK2, TET2 and MYD88 gene mutations in BCR-ABL–negative myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms
- Hematology Department and Transfusion Medicine Unit, School of Medical Sciences, Universiti Sains Malaysia
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia
- Department of Biomedical Science and Physiology, School of Life Sciences, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, WV1 1LY, UK
Abstract
Introduction: BCR-ABL-negative myeloproliferative neoplasms (MPNs)—including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)—together with myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), are clinically heterogeneous chronic myeloid disorders. These entities are predominantly driven by somatic mutations in Janus kinase 2 (JAK2), calreticulin (CALR) and myeloproliferative leukemia (MPL) genes. Although JAK2 exon 12 and MYD88 mutations are reported less frequently, they may still contribute to disease pathogenesis and progression. This study aimed to investigate the mutational landscape of JAK2 (V617F and exon 12), TET2 and MYD88 in a Malaysian cohort of patients with BCR-ABL-negative MPNs or MDS/MPNs.
Methods: A total of 54 patients with BCR-ABL-negative MPNs (n = 48) or MDS/MPNs (n = 6) were prospectively enrolled between 2015 and 2018. Genomic DNA isolated from peripheral blood was analyzed by polymerase chain reaction followed by Sanger sequencing.
Results: The JAK2 V617F mutation was identified in 81.5 % of cases, including 90 % of PV, 84.6 % of ET and 80 % of PMF patients. Among the JAK2 exon 12 variants detected, D544N and c.1194+12G>A were consistently observed on repeat sequencing. These variants, previously reported by other investigators, were likewise present in our cohort, reinforcing their potential relevance to the molecular profile of MPNs. No pathogenic variants were found in TET2 exons 1 or 7. In addition, a known MYD88 intronic single-nucleotide polymorphism (rs4988457) was detected in three MPN patients (PV = 2, ET = 1), all of whom were co-mutated for JAK2 V617F and/or an exon 12 variant.
Conclusion: This study confirms the central role of JAK2 V617F in BCR-ABL-negative MPNs and documents rare but potentially significant JAK2 exon 12 co-mutations. The presence of the MYD88 rs4988457 variant supports a possible inflammatory component in MPN pathogenesis. Together, these findings underscore the value of comprehensive mutational screening and provide further insight into the molecular complexity of MPNs, with implications for diagnosis, risk stratification and the development of targeted therapies.