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Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy

1
Département de pharmacologie-physiologie, Université de Montréal, Montréal, QC H3C 3J7, Canada
2
Service d’hématologie-oncologie, Centre de recherche, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada
*
Author to whom correspondence should be addressed.
Received: 25 January 2020 / Revised: 18 February 2020 / Accepted: 27 February 2020 / Published: 1 March 2020
(This article belongs to the Special Issue Epigenetic Cancer Therapy: Targeting DNA and Histone Methylation)
Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires the complete eradication of the leukemic stem cells (LSCs). One aspect of LSCs that is poorly understood is their low frequency in the total population of leukemic cells in AML patients. After each cell division of LSCs, most of the daughter cells lose their capacity for self-renewal. Investigations into the role of Isocitrate dehydrogenase (IDH) mutations in AML provide some insight on the regulation of the proliferation of LSCs. The primary role of IDH is to convert isocitrate to alpha-keto-glutarate (α-KG). When IDH is mutated, it converts α-KG to 2-hydroxyglutarate (2-HG), an inhibitor of the TET pathway and Jumonji-C histone demethylases (JHDMs). The demethylating action of these enzymes removes the epigenetic gene-silencing markers, DNA methylation, H3K27me3 and H3K9me2 and can lead to the differentiation of LSCs. This enzymatic action is blocked by 2-HG in mutated IDH (mut-IDH) AML patients, who can be induced into remission with antagonists of 2-HG. These observations suggest that there exists in cells a natural enzymatic mechanism that uses demethylation to reverse epigenetic gene-silencing, leading to a loss of the self-renewal capacity of LSCs. This mechanism limits the proliferative potential of LSCs. Epigenetic agents that inhibit DNA and histone methylation exhibit a synergistic antineoplastic action on AML cells. It is possible that the therapeutic potential of this epigenetic therapy may be enhanced by demethylation enzymes, resulting in a very effective treatment for AML. View Full-Text
Keywords: leukemic stem cells; self-renewal; epigenetics; DNA methylation; histone methylation; 5-aza-2′-deoxycytidine; 3-deazaplanocin-A leukemic stem cells; self-renewal; epigenetics; DNA methylation; histone methylation; 5-aza-2′-deoxycytidine; 3-deazaplanocin-A
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MDPI and ACS Style

Momparler, R.L.; Côté, S.; Momparler, L.F. Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy. Epigenomes 2020, 4, 3. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4010003

AMA Style

Momparler RL, Côté S, Momparler LF. Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy. Epigenomes. 2020; 4(1):3. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4010003

Chicago/Turabian Style

Momparler, Richard L.; Côté, Sylvie; Momparler, Louise F. 2020. "Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy" Epigenomes 4, no. 1: 3. https://0-doi-org.brum.beds.ac.uk/10.3390/epigenomes4010003

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