Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms.

Publisher: Nature Publishing Group, Specialist Journals Country of Publication: England NLM ID: 8704895 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5551 (Electronic) Linking ISSN: 08876924 NLM ISO Abbreviation: Leukemia Subsets: MEDLINE

Publication: 2000- : London : Nature Publishing Group, Specialist Journals
Original Publication: [Baltimore, Md.] : Williams & Wilkins, [c1987-

Leukemia*/genetics ; Myeloproliferative Disorders* ; Neoplasms*; Animals ; Germ Cells/metabolism ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Peroxidase/genetics ; Peroxidase/metabolism

Myeloperoxidase (MPO) gene alterations with variable clinical penetrance have been found in hereditary MPO deficiency, but their leukemia association in patients and carriers has not been established. Germline MPO alterations were found to be significantly enriched in myeloid neoplasms: 28 pathogenic/likely pathogenic variants were identified in 100 patients. The most common alterations were c.2031-2 A > C, R569W, M519fs* and Y173C accounting for about half of the cases. While functional experiments showed that the marrow stem cell pool of Mpo ^-/- mice was not increased, using competitive repopulation demonstrated that Mpo ^-/- grafts gained growth advantage over MPO wild type cells. This finding also correlated with increased clonogenic potential after serial replating in the setting of H 2 O 2 -induced oxidative stress. Furthermore, we demonstrated that H 2 O 2 -induced DNA damage and activation of error-prone DNA repair may result in secondary genetic damage potentially predisposing to leukemia leukemic evolution. In conclusion, our study for the first time demonstrates that germline MPO variants may constitute risk alleles for MN evolution.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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R35 HL135795 United States HL NHLBI NIH HHS; R01 HL132071 United States HL NHLBI NIH HHS; R01 CA257544 United States CA NCI NIH HHS

BBX060AN9V (Hydrogen Peroxide)
EC 1.11.1.7 (Peroxidase)

Date Created: 20220627 Date Completed: 20220803 Latest Revision: 20220808

20240105

10.1038/s41375-022-01630-0

35761024