2. Academic Validation
  3. Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms

Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms

  • Leukemia. 2022 Aug;36(8):2086-2096. doi: 10.1038/s41375-022-01630-0.
Sunisa Kongkiatkamon 1 2,  Laila Terkawi 1,  Yihong Guan 1,  Vera Adema 1,  Metis Hasipek 1,  Tatiana Dombrovski 3,  Milo Co 1,  Wencke Walter 4,  Hassan Awada 1,  Yvonne Parker 1,  Stephan Hutter 4,  Simona Pagliuca 1,  Carmelo Gurnari 1,  Heesun J Rogers 5,  Manja Meggendorfer 4,  Daniel J Lindner 1,  Torsten Haferlach 4,  Valeria Visconte 1,  Thomas LaFramboise 3,  Babal K Jha 1,  Jaroslaw P Maciejewski 6
Affiliations

Affiliations

  • 1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 2 Research Unit in Translational Hematology, Division of Hematology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • 3 Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
  • 4 MLL Munich Leukemia Laboratory, Munich, Germany.
  • 5 Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
  • 6 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. [email protected].
PMID: 35761024 DOI: 10.1038/s41375-022-01630-0
Abstract

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 H2O2-induced oxidative stress. Furthermore, we demonstrated that H2O2-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.

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