Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy
Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires<i> </i>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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
|
| Series: | Epigenomes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-4655/4/1/3 |
| _version_ | 1797757826242707456 |
|---|---|
| author | Richard L. Momparler Sylvie Côté Louise F. Momparler |
| author_facet | Richard L. Momparler Sylvie Côté Louise F. Momparler |
| author_sort | Richard L. Momparler |
| collection | DOAJ |
| description | Most patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires<i> </i>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. |
| first_indexed | 2024-03-12T18:21:07Z |
| format | Article |
| id | doaj.art-5df0bc6fcadf42a0b4471690c760247c |
| institution | Directory Open Access Journal |
| issn | 2075-4655 |
| language | English |
| last_indexed | 2024-03-12T18:21:07Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Epigenomes |
| spelling | doaj.art-5df0bc6fcadf42a0b4471690c760247c2023-08-02T08:55:25ZengMDPI AGEpigenomes2075-46552020-03-0141310.3390/epigenomes4010003epigenomes4010003Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for ChemotherapyRichard L. Momparler0Sylvie Côté1Louise F. Momparler2Département de pharmacologie-physiologie, Université de Montréal, Montréal, QC H3C 3J7, CanadaService d’hématologie-oncologie, Centre de recherche, CHU Sainte-Justine, Montreal, QC H3T 1C5, CanadaService d’hématologie-oncologie, Centre de recherche, CHU Sainte-Justine, Montreal, QC H3T 1C5, CanadaMost patients with acute myeloid leukemia (AML) have a poor prognosis. Curative therapy of AML requires<i> </i>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.https://www.mdpi.com/2075-4655/4/1/3leukemic stem cellsself-renewalepigeneticsdna methylationhistone methylation5-aza-2′-deoxycytidine3-deazaplanocin-a |
| spellingShingle | Richard L. Momparler Sylvie Côté Louise F. Momparler Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy Epigenomes leukemic stem cells self-renewal epigenetics dna methylation histone methylation 5-aza-2′-deoxycytidine 3-deazaplanocin-a |
| title | Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy |
| title_full | Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy |
| title_fullStr | Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy |
| title_full_unstemmed | Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy |
| title_short | Epigenetic Modulation of Self-Renewal Capacity of Leukemic Stem Cells and Implications for Chemotherapy |
| title_sort | epigenetic modulation of self renewal capacity of leukemic stem cells and implications for chemotherapy |
| topic | leukemic stem cells self-renewal epigenetics dna methylation histone methylation 5-aza-2′-deoxycytidine 3-deazaplanocin-a |
| url | https://www.mdpi.com/2075-4655/4/1/3 |
| work_keys_str_mv | AT richardlmomparler epigeneticmodulationofselfrenewalcapacityofleukemicstemcellsandimplicationsforchemotherapy AT sylviecote epigeneticmodulationofselfrenewalcapacityofleukemicstemcellsandimplicationsforchemotherapy AT louisefmomparler epigeneticmodulationofselfrenewalcapacityofleukemicstemcellsandimplicationsforchemotherapy |