TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

Bensberg, Maike; Rundquist, Olof; Selimović, Aida; Lagerwall, Cathrine; Benson, Mikael; Gustafsson, Mika; Vogt, Hartmut; Lentini, Antonio; Nestor, Colm E.

doi:10.1073/pnas.2110758118

Cited by 38 publications

(20 citation statements)

References 88 publications

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“…Moreover, the higher hmdC levels after AzadC treatment also correlated in the HL-60 with higher efficacy to induce apoptosis compared to AzaC. Interestingly, AzaC treatment also restores TET2 expression and hmdC in a different leukemic context (T-cell acute lymphoblastic leukemia), which results in rapid cell death [ 41 ], suggesting that TET activity is an important factor for the efficiency of AzaC or AzadC treatment in inducing cell death. However, whether enhanced TET activity is simply a result of successful cellular reprogramming after AzaC or AzadC treatment or a prerequisite for AzaC- or AzadC-induced cell death of cancer cells, whether there are a specific genomic context and threshold of hmdC formation and why AzaC in contrast to AzadC was not able to restore hmdC in the MOLM-13 remain to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

et al. 2022

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Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2’-deoxycytidine by methylating 2’-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity toward AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double-strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis efficiently in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response toward AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.

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Section: Discussionmentioning

confidence: 99%

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

et al. 2022

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“…The only cellular marker in our study that clearly correlated with the failed induction of apoptosis after AzaC treatment was the amount of global hmdC. Interestingly, AzaC treatment did restore TET2 expression and hmdC in a different leukemic context (T-cell acute lymphoblastic leukemia), which resulted in rapid cell death [35], suggesting that TET activity is an important factor for the efficiency of AzaC or AzadC treatment in inducing cell death. However, whether enhanced TET activity is simply a result of successful cellular reprogramming after AzaC or AzadC treatment or a prerequisite for AzaC or AzadC induced cell death of cancer cells and why AzaC in contrast to AzadC was not able to restore hmdC in the MOLM-13 remains to be investigated.…”

Section: Discussionmentioning

confidence: 95%

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Aumer

Gremmelmaier

Runtsch

et al. 2022

Preprint

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Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2'-deoxycytidine by methylating 2'-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity towards AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response towards AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.

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“…However, the treatment with the DNA demethylating agent, 5-azacytidine (5-aza) leads to a strong de-repression of ERVs in all the examined species, including the hypomethylated chicken fibroblasts, thus confirming that DNA methylation is a conserved mechanism for repressing ERVs in vertebrates ( 19 ). The de-repression of ERVs achieved after 5-aza treatment was observed in many different physiological and pathological contexts ( 20 – 26 ). As a matter of fact, female mice deficient for the DNA demethylase Tet1 experience premature infertility consistent with premature ovarian failure that correlates with Line 1 and ERV activation ( 27 ).…”

Section: Regulation Of Erv Expression At Transcriptional and Post-tra...mentioning

confidence: 99%

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Giorgio

Xodo

2022

Front. Immunol.

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Bi-directional transcription of Human Endogenous Retroviruses (hERVs) is a common feature of autoimmunity, neurodegeneration and cancer. Higher rates of cancer incidence, neurodegeneration and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties. An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of dsRNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS–STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

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TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia

Cited by 38 publications

References 88 publications

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

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