G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent

Tonelli, Roberto; Sartini, Roberta; Fronza, Raffaele; Freccero, Francesca; Franzoni, Monica; Dongiovanni, Danilo Nicola; Ballarini, Marco; Ferrari, Sara; D’Apolito, Maria; Cola, Gabriella Di; Capranico, Giovanni; Khobta, Andriy; Campanini, R.; Paolucci, Paolo; Minucci, Saverio; Pession, Andrea

doi:10.1038/sj.leu.2404221

Cited by 23 publications

(18 citation statements)

References 9 publications

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“…On the other hand, although K562 and M07 cells were resistant to VPA-induced apoptosis, they still have undergone cell cycle arrest (Figure 1j and Supplementary Figure 2c). The decrease in the proliferation of DS-AMKL cell lines upon VPA treatment is not due to differentiation (Supplementary Figure 2d), which is in accordance to previous studies in AML [29]. …”

Section: Resultssupporting

confidence: 91%

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

et al. 2013

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Histone deacetylase (HDAC)-inhibitors (HDACis) are well characterized anti-cancer agents with promising results in clinical trials. However, mechanistically little is known regarding their selectivity in killing malignant cells while sparing normal cells. Gene expression-based chemical genomics identified HDACis as being particularly potent against Down syndrome associated myeloid leukemia (DS-AMKL) blasts. Investigating the anti-leukemic function of HDACis revealed their transcriptional and posttranslational regulation of key autophagic proteins, including ATG7. This leads to suppression of autophagy, a lysosomal degradation process that can protect cells against damaged or unnecessary organelles and protein aggregates. DS-AMKL cells exhibit low baseline autophagy due to mTOR activation. Consequently, HDAC inhibition repressed autophagy below a critical threshold, which resulted in accumulation of mitochondria, production of reactive oxygen species, DNA-damage and apoptosis. Those HDACi-mediated effects could be reverted upon autophagy activation or aggravated upon further pharmacological or genetic inhibition. Our findings were further extended to other major acute myeloid leukemia subgroups with low basal level autophagy. The constitutive suppression of autophagy due to mTOR activation represents an inherent difference between cancer and normal cells. Thus, via autophagy suppression, HDACis deprive cells of an essential pro-survival mechanism, which translates into an attractive strategy to specifically target cancer cells.

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Section: Resultssupporting

confidence: 91%

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

et al. 2013

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“…Inhibition of histone deacetylase by valproic acid induced G 1 cell-cycle arrest and apoptosis in cell lines and patient samples expressing MLL-AF9. 74 This effect is mediated by p21.…”

Section: Histone Deacetylase and Dna Methyltransferase Inhibitorsmentioning

confidence: 99%

“…Inhibition of histone deacetylase by valproic acid induced G 1 cell-cycle arrest and apoptosis in cell lines and patient samples expressing MLL-AF9. 74 This effect is mediated by p21.The DNA methyltransferase inhibitor decitabine induces apoptosis of MLL leukemia cells in vitro. Although demethylating agents are able to restore expression of a variety of different genes, one confirmed candidate gene of decitabine is the tumor suppressor Fragile Histidine Triad gene (FHIT).…”

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confidence: 99%

Therapeutic targeting of MLL

Liedtke

Cleary²

2009

Blood

100

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Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) protooncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes. (Blood. 2009;113: 6061-6068) IntroductionThe mixed lineage leukemia (MLL) gene is frequently rearranged in acute myeloid and lymphoblastic leukemias in adults and children 1,2 and identifies a patient population with a particularly poor prognosis. 3 Leukemogenic MLL rearrangements occur in a variety of forms, including reciprocal chromosomal translocations and partial tandem duplications of internal coding regions. 4 The MLL gene encodes a histone methyltransferase (HMT) implicated in epigenetic regulation of transcription that is critical for normal embryonic development and hematopoiesis. 5 Among the most widely studied target genes of MLL transcriptional regulation are HOX genes, which themselves are implicated in the malignant transformation of hematopoietic progenitors. 6,7 In leukemias, chromosomal translocations fuse the aminoterminal part of MLL in-frame to one of more than 50 partner proteins. 8 The most common translocations in acute lymphoblastic leukemia (ALL) are t(4;11) and t(11;19), resulting in expression of MLL-AF4 and MLL-ENL, respectively, whereas acute myeloid leukemia (AML) is frequently associated with t(9;11) and t(6;11) giving rise to MLL-AF9 and MLL-AF6, respectively. All MLL fusion proteins retain the amino-terminal portion containing AT hooks and the CxxC domain of MLL, thus preserving DNAbinding activity. In contrast, a region with transactivating potential, the plant homeodomain (PHD) fingers, and the suppressor of variegation-enhancer of zeste-trithorax (SET) domain, which mediates histone H3 lysine 4 (H3K4) methylation, are lost. Although loss of the carboxy-terminal regions of MLL in chimeric oncoproteins would be predicted to result in abrogation of transactivation and HMT functions, transforming MLL fusion proteins function as transcriptional regulators and induce aberrant expression of downstream MLL targets, including HOX genes. 9,10 The precise mechanism for this aberrant transcriptional activity is not known but involves formation...

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“…Our results suggest that down-regulation of Gata2 may contribute to leukaemogenic transformation and that reactivation of Gata2 could be a novel treatment strategy in patients with acute leukaemias. Moreover, further analysis of the transcriptional repression program associated with the leukaemic phenotype may provide new mechanistic insights into the efficacy of de-repressive epigenetic therapies such as inhibition of histone deacetylases and DNA-methyltransferases [53], [54]. Finally, the integrated genome-wide approach employed in this study should be readily adaptable to study transcriptional reprogramming in other leukaemias as well as many solid tumours.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

et al. 2011

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Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.

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G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent

Cited by 23 publications

References 9 publications

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

Histone deacetylase inhibitors induce apoptosis in myeloid leukemia by suppressing autophagy

Therapeutic targeting of MLL

Genome-Wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia

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