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Loss of H3K27 methylation identifies poor outcomes in adult-onset acute leukemia.
- Source :
-
Clinical epigenetics [Clin Epigenetics] 2021 Jan 28; Vol. 13 (1), pp. 21. Date of Electronic Publication: 2021 Jan 28. - Publication Year :
- 2021
-
Abstract
- Background: Acute leukemia is an epigenetically heterogeneous disease. The intensity of treatment is currently guided by cytogenetic and molecular genetic risk classifications; however these incompletely predict outcomes, requiring additional information for more accurate outcome predictions. We aimed to identify potential prognostic implications of epigenetic modification of histone proteins, with a focus on H3K4 and H3K27 methylation marks in relation to mutations in chromatin, splicing and transcriptional regulators in adult-onset acute lymphoblastic and myeloid leukemia.<br />Results: Histone 3 lysine 4 di- and trimethylation (H3K4me2, H3K4me3) and lysine 27 trimethylation (H3K27me3) mark expression was evaluated in 241 acute myeloid leukemia (AML), 114 B-cell acute lymphoblastic leukemia (B-ALL) and 14T-cell ALL (T-ALL) patient samples at time of diagnosis using reverse phase protein array. Expression levels of the marks were significantly lower in AML than in B and T-ALL in both bone marrow and peripheral blood, as well as compared to normal CD34+ cells. In AML, greater loss of H3K27me3 was associated with increased proliferative potential and shorter overall survival in the whole patient population, as well as in subsets with DNA methylation mutations. To study the prognostic impact of H3K27me3 in the context of cytogenetic aberrations and mutations, multivariate analysis was performed and identified lower H3K27me3 level as an independent unfavorable prognostic factor in all, as well as in TP53 mutated patients. AML with decreased H3K27me3 demonstrated an upregulated anti-apoptotic phenotype. In ALL, the relative quantity of histone methylation expression correlated with response to tyrosine kinase inhibitor in patients who carried the Philadelphia cytogenetic aberration and prior smoking behavior.<br />Conclusion: This study shows that proteomic profiling of epigenetic modifications has clinical implications in acute leukemia and supports the idea that epigenetic patterns contribute to a more accurate picture of the leukemic state that complements cytogenetic and molecular genetic subgrouping. A combination of these variables may offer more accurate outcome prediction and we suggest that histone methylation mark measurement at time of diagnosis might be a suitable method to improve patient outcome prediction and subsequent treatment intensity stratification in selected subgroups.
- Subjects :
- Age of Onset
Aged
Antigens, CD34 metabolism
Case-Control Studies
Chromosome Aberrations statistics & numerical data
DNA Methylation
Epigenomics
Female
Gene Expression Regulation, Leukemic genetics
Histone Code genetics
Histones genetics
Humans
Jumonji Domain-Containing Histone Demethylases genetics
Leukemia, Myeloid, Acute blood
Leukemia, Myeloid, Acute pathology
Male
Middle Aged
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma blood
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Prognosis
Protein Array Analysis methods
Proteomics
Survival Rate
Transcription Factors genetics
Histones metabolism
Leukemia, Myeloid, Acute genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1868-7083
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical epigenetics
- Publication Type :
- Academic Journal
- Accession number :
- 33509276
- Full Text :
- https://doi.org/10.1186/s13148-021-01011-x