BRCA2 promoter hypermethylation as a biomarker for the leukemic transformation of myeloproliferative neoplasms

Aim: To characterize the actionable biomarker for leukemic transformation (LT) of myeloproliferative neoplasms (MPNs) at the DNA damage repair promoter methylation level. Materials & methods: Bioinformatic analysis and experimental validation were performed to identify the MPNs-LT specific biomarker out of the promoter methylation of 236 DNA damage repair genes with GSE42042 dataset and an in-house cohort of 80 MPNs. Results: Hypermethylation of BRCA2 promoter was characterized as the JAK2 mutation-independent epigenetic marker for MPNs-LT and repressed mRNA and protein expression, leading to olaparib hypersensitivity in the leukemic cells from MPNs-LT. Conclusion: Expressional silence of BRCA2 by promoter methylation compels the homologous recombination deficiency and vulnerability to PARP inhibition and serves as an actionable marker for targeted therapy for MPNs-LT. Plain language summary Leukemic transformation is a difficulty of myeloproliferative tumors, known as myeloproliferative neoplasms (MPNs). It is possible that DNA damage repair (DDR) dysregulation plays a very important role during the change process. To show the leukemic transformation-related change in DDR-related genes, the authors compared the promoter methylation patterns of DDR genes between leukemic transformed MPNs and long-lasting MPNs in two independent MPN associates/groups of people. The authors identified BRCA2 as the most significantly epigenetically silenced DDR gene during the leukemic transformation phase of disease. The study found that promoter hypermethylation of BRCA2 is an epigenetic marker for the leukemic transformation of MPNs, although its clinical use awaits further experimentation.