Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Tsai, Chiou-Tsun; So, Chi Wai Eric

doi:10.1038/onc.2016.315

Cited by 38 publications

(34 citation statements)

References 72 publications

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“…Finally, ASH1 knockdown caused a decrease in mRNA levels of these profibrotic genes, suggesting that ASH1 has a significant role in the activation of fibroblasts during fibrosis. It is likely that similar mechanisms are involved in the alterations in gene expression during CAF transdifferentiation, but future studies are necessary to determine the specific roles of histone methyltransferase-mediated gene activation in these fibroblasts, especially since inhibitors of these histone methyltransferases are being developed for use in cancer [65,[67][68].…”

Section: Regulation Of Gene Expression In Stromal Cells By Histone Momentioning

confidence: 99%

Epigenetic Control of the Tumor Microenvironment

2016

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Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumorassociated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanismtargeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment.

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Section: Regulation Of Gene Expression In Stromal Cells By Histone Momentioning

confidence: 99%

Epigenetic Control of the Tumor Microenvironment

2016

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“…The most common MLL fusion partners include AF4, AF9, ENL, AF10 and ELL, which together account for over 80% of MLL‐rearranged AML and 4% of all AML patients . These most recurrent MLL fusions share a similar downstream pathway, including aberrant upregulated expression of MLL target genes and histone modification genes, as shown by several studies …”

Section: Introductionmentioning

confidence: 87%

“…9 These most recurrent MLL fusions share a similar downstream pathway, including aberrant upregulated expression of MLL target genes and histone modification genes, as shown by several studies. [10][11][12][13][14] Studies have demonstrated that enforced expression of MLL-AF9 fusion protein could transform the non-self-renewing granulocyte/macrophage progenitors (GMP) into leukemia stem cells (LSC) by activating the expression of Hox proteins. 15 Consistently, the coexpression of Homeobox proteins Hoxa9/Meis1 or Meis1/Pbx3 is sufficient to immortalize hematopoietic progenitor cells (HPC) and induce leukemogenesis, [16][17][18][19] indicating a bridge/mediator role of transcription factors in MLL fusion-induced leukemic transformation and progression.…”

Section: Introductionmentioning

confidence: 99%

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

Chu

Chen

et al. 2019

Cancer Science

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Molecular genetic changes in acute myeloid leukemia (AML) play crucial roles in leukemogenesis, including recurrent chromosome translocations, epigenetic/spliceosome mutations and transcription factor aberrations. Six1, a transcription factor of the Sine oculis homeobox (Six) family, has been shown to transform normal hematopoietic progenitors into leukemia in cooperation with Eya. However, the specific role and the underlying mechanism of Six1 in leukemia maintenance remain unexplored. Here, we showed increased expression of SIX1 in AML patients and murine leukemia stem cells (c‐Kit+ cells, LSCs). Importantly, we also observed that a higher level of Six1 in human patients predicts a worse prognosis. Notably, knockdown of Six1 significantly prolonged the survival of MLL‐AF9‐induced AML mice with reduced peripheral infiltration and tumor burden. AML cells from Six1‐knockdown (KD) mice displayed a significantly decreased number and function of LSC, as assessed by the immunophenotype, colony‐forming ability and limiting dilution assay. Further analysis revealed the augmented apoptosis of LSC and decreased expression of glycolytic genes in Six1 KD mice. Overall, our data showed that Six1 is essential for the progression of MLL‐AF9‐induced AML via maintaining the pool of LSC.

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“…In conclusion, our results show that the major role of dKDM2 is the epigenetic regulation of circadian behavior, instead of normal development. Because small chemical inhibitors have been actively developed to specifically target KDMs in recent years (HOFFMANN et al 2012;THINNES et al 2014;MORERA et al 2016;SONG et al 2016;TSAI and SO 2017), our results suggest that it will be important to determine whether the KDM2 inhibitors may affect the circadian clocks in both Drosophila and mammals. It will be necessary to perform detailed analyses of changes of epigenetic marks in neurons from dKdm2 mutants, particularly on the genes involved in regulating circadian clocks and other behaviors in the future.…”

Section: Role Of Dkdm2 In Regulating H2a Ubiquitination the Histone mentioning

confidence: 99%

The lysine demethylase dKDM2 is non-essential for viability, but regulates circadian rhythms in Drosophila

Zheng

Xue

Ren

et al. 2018

Preprint

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Post-translational modification of histones, such as histone methylation controlled by specific methyltransferases and demethylases, play critical roles in modulating chromatin dynamics and transcription in eukaryotes. Misregulation of histone methylation can lead to aberrant gene expression, thereby contributing to abnormal development and diseases such as cancer. As such, the mammalian lysine-specific demethylase 2 (KDM2) homologs, KDM2A and KDM2B, are either oncogenic or tumor suppressive, depending on specific pathological contexts. However, the role of KDM2 proteins during development in the whole organisms remains poorly understood. Unlike vertebrates, Drosophila has only one KDM2 homolog (dKDM2), but its functions in vivo remain elusive due to the complexities of the existing mutant alleles. To address this problem, we have generated two dKdm2 null alleles using the CRISPR/Cas9 technique.These dKdm2 homozygous mutants are fully viable and fertile, with no developmental defects observed under laboratory conditions. However, the dKdm2 null mutant adults display defects in circadian rhythms. Most of the dKdm2 mutants become arrhythmic under constant darkness, while the circadian period of the rhythmic mutant flies is approximately one hour shorter than the control. Interestingly, opposite defects are observed when dKDM2 is overexpressed in circadian pacemaker neurons. Taken together, these results demonstrate that dKdm2 is not essential for viability; instead, dKDM2 protein plays important roles in regulating circadian rhythms in Drosophila. Further analyses of the molecular mechanisms of how dKDM2 and its orthologs in vertebrates regulate circadian rhythms will advance our understanding of the epigenetic regulations of circadian clocks.

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Epigenetic therapies by targeting aberrant histone methylome in AML: molecular mechanisms, current preclinical and clinical development

Cited by 38 publications

References 72 publications

Epigenetic Control of the Tumor Microenvironment

Epigenetic Control of the Tumor Microenvironment

Six1 regulates leukemia stem cell maintenance in acute myeloid leukemia

The lysine demethylase dKDM2 is non-essential for viability, but regulates circadian rhythms in Drosophila

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