Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms.
Fiche publication
Date publication
août 2022
Journal
Leukemia
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PAGLIUCA Simona
Tous les auteurs :
Kongkiatkamon S, Terkawi L, Guan Y, Adema V, Hasipek M, Dombrovski T, Co M, Walter W, Awada H, Parker Y, Hutter S, Pagliuca S, Gurnari C, Rogers HJ, Meggendorfer M, Lindner DJ, Haferlach T, Visconte V, LaFramboise T, Jha BK, Maciejewski JP
Lien Pubmed
Résumé
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 HO-induced oxidative stress. Furthermore, we demonstrated that HO-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.
Mots clés
Animals, Germ Cells, metabolism, Humans, Hydrogen Peroxide, pharmacology, Leukemia, genetics, Mice, Myeloproliferative Disorders, Neoplasms, Peroxidase, genetics
Référence
Leukemia. 2022 08;36(8):2086-2096