Related Experiment Video
Updated: Sep 6, 2025
Fast and Specific Assessment of the Halogenating Peroxidase Activity in Leukocyte-enriched Blood Samples
Published on: July 28, 2016
Rare germline alterations of myeloperoxidase predispose to myeloid neoplasms
Sunisa Kongkiatkamon1,2, Laila Terkawi1, Yihong Guan1
1Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
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.
Insights
Germline mutations in the myeloperoxidase (MPO) gene are linked to myeloid neoplasms. These MPO variants may increase leukemia risk by promoting cell growth under oxidative stress.
Area of Science:
- Genetics
- Hematology
- Oncology
Background:
- Hereditary myeloperoxidase (MPO) deficiency involves gene alterations with variable clinical penetrance.
- The association between germline MPO alterations and leukemia risk in patients and carriers remains unclear.
Purpose of the Study:
- To investigate the enrichment of germline MPO alterations in myeloid neoplasms (MN).
- To explore the functional impact of MPO deficiency on hematopoietic stem cell function and leukemic evolution.
Main Methods:
- Genomic analysis of germline MPO variants in 100 myeloid neoplasm patients.
- Functional studies using Mpo knockout (Mpo-/-) mice, including competitive repopulation assays.
- Assessment of cellular response to hydrogen peroxide (H2O2)-induced oxidative stress and DNA damage.
Main Results:
- Germline MPO alterations were significantly enriched in myeloid neoplasms, with 28 pathogenic/likely pathogenic variants identified.
- Mpo-/- hematopoietic stem cells exhibited a growth advantage in competitive repopulation assays and increased clonogenic potential under oxidative stress.
- H2O2-induced DNA damage and error-prone repair in MPO-deficient cells may lead to secondary genetic alterations, potentially predisposing to leukemia.
Conclusions:
- Germline MPO variants are associated with myeloid neoplasms.
- MPO deficiency can confer a growth advantage to hematopoietic stem cells, particularly under oxidative stress.
- Germline MPO variants represent potential risk alleles for the evolution of myeloid neoplasms and leukemia.
Related Concept Videos
02:23Abnormal Proliferation
01:20Mismatch Repair
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
01:33Pleiotropy
01:15Differentiation of Common Myeloid Progenitor Cells
01:27Protein Import into the Peroxisomes
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...