BRCA2 Promoter Hypermethylation as a Biomarker for the Leukemic Transformation of Myeloproliferative Neoplasms

Abstract

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.

Keywords::

• homologous recombination deficiency
• myeloproliferative neoplasms
• promoter methylation

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2022-0025

Author Contributions

C Yang: formal analysis, methodology, writing – original draft. Q Zhang: investigation, methodology. X Tang: investigation, methodology. B Wang: investigation, methodology. G Tang: investigation, writing – review and editing. Z Wu: conceptualization, funding acquisition, writing – original draft, writing – review and editing.

Financial & competing interests disclosure

This study was funded by the National Natural Science Foundation of China [81802993], Shanghai Municipal Key Clinical Specialty [shslczdzk03303] and the Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate approval from the Institutional Review Boards of Huashan Hospital of Fudan University and Navy Military Medical University, China, and followed the principles outlined in the Declaration of Helsinki of 1975 as revised in 1996 for all human or animal experimental investigations.

Additional information

Funding

This study was funded by the National Natural Science Foundation of China [81802993], Shanghai Municipal Key Clinical Specialty [shslczdzk03303] and the Innovation Group Project of Shanghai Municipal Health Commission [2019CXJQ03]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.