Anti-leukemic effects of histone deacetylase (HDAC) inhibition in acute lymphoblastic leukemia (ALL) cells: Shedding light on mitigating effects of NF-κB and autophagy on panobinostat cytotoxicity

2020 ◽  
Vol 875 ◽  
pp. 173050 ◽  
Author(s):  
Mahdieh Mehrpouri ◽  
Ava Safaroghli-Azar ◽  
Atieh pourbagheri-Sigaroodi ◽  
Majid Momeny ◽  
Davood Bashash
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Lymphoblastic Leukemia ◽  
Hdac Inhibition

Novel SIRT1 Agonists, SRT501 and SRT2183, Induce Expression of DNA Repair Genes and Apoptosis of Ph− Acute Lymphoblastic Leukemia Cells Alone and in Combination with the HDAC Inhibitor LBH589..

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3083-3083
Author(s):  
Anna Scuto ◽  
Mark Kirschbaum ◽  
Jennifer M Cermak ◽  
Peter Atadja ◽  
Richard Jove
Keyword(s):  
Dna Damage ◽  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
Histone Deacetylase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Growth Arrest ◽  
Mrna Levels ◽  
Damage Response

Abstract Abstract 3083 Poster Board III-20 Histone Deacetylase Inhibitors (HDACi) such as LBH589, which inhibit the zinc containing catalytic domain of HDAC of classes I, II, and IV, demonstrate activity against various malignancies, particularly lymphoid malignancies. SIRT1 is an NAD+ dependent class III histone deacetylase, which deacetylates histones as well as non-histone proteins and is not affected directly by HDACi such as LBH589. It remains controversial whether inhibition of SIRT1 or its activation is more efficacious in anticancer therapy. We have studied the activity of two novel SIRT1 activators, SRT501 and SRT2183, in Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) cell lines. Both pre B (NALM-6, Reh) and T cell (MOLT-4) ALL lines were treated with either SRT501 or SRT2183, as well as in combination with LBH589 and evaluated for biological and gene expression responses. SRT501 induced growth arrest and apoptosis at doses ranging from 10-100 uM, with even the lowest doses inhibiting growth at 72 hours. SRT2183 is much more potent, with growth arrest and apoptosis induced at doses ranging from 1-20 uM. PCR array analysis revealed that SRT2183 treatment leads to increased mRNA levels of pro-apoptosis, growth arrest, and DNA damage response genes. We have previously demonstrated that the activity of LBH589 is mediated in part through upregulation or acetylation of proteins involved in the DNA damage response pathways. Quantitative real-time PCR confirms that the combination of LBH589 with SRT2183 leads to significantly higher expression of GADD45A and GADD45G than either agent alone. The combination of LBH589 plus SRT2183 showed enhanced inhibition of c-Myc protein levels, phosphorylation of H2A.X, and interestingly, increased acetylation of p53 (acetylation of p53 was not seen with SRT2183 alone). In summary, the novel SIRT1 activators SRT501 and SRT2183 show growth inhibitory and pro-apoptotic activity in Ph- ALL alone and enhanced activity in combination with LBH589. Clinical studies of these agents, particularly in combination with HDACi are warranted. Disclosures Kirschbaum: Novartis: Consultancy. Cermak:Sirtris: Employment. Atadja:Novartis: Employment.

scholarly journals TAL1/SCL is downregulated upon histone deacetylase inhibition in T-cell acute lymphoblastic leukemia cells

Leukemia ◽  
2011 ◽  
Vol 25 (10) ◽  
pp. 1578-1586 ◽  
Author(s):  
B A Cardoso ◽  
S F de Almeida ◽  
A B A Laranjeira ◽  
M Carmo-Fonseca ◽  
J A Yunes ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Histone Deacetylase ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Histone Deacetylase Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

Histone Deacetylase Inhibitor Induces FPGS mRNA Expression in Childhood B-Precursor and T Acute Lymphoblastic Leukemia: Implication of Combination Therapy with Methotrexate To Enhance Cytotoxicity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 864-864 ◽  
Author(s):  
Guy J. Leclerc ◽  
Julio C. Barredo
Keyword(s):  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Mrna Expression ◽  
Histone Deacetylase ◽  
Chromatin Remodeling ◽  
Binding Sites ◽  
Histone Deacetylase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Atp Binding ◽  
Deacetylase Inhibitor

Abstract Methotrexate (MTX) is an antifolate widely used to treat childhood acute lymphoblastic leukemia (ALL). MTX is retained within cells as long-chain polyglutamates (MTX-PGs), after metabolism by the enzyme folylpoly-γ-glutamate synthetase (FPGS). Intracellular retention of MTX-PGs results in enhanced cytotoxicity due to prolonged inhibition of dihydrofolate reductase (DHFR), and the additional inhibition of thymidylate synthetase (TS). The FPGS gene was shown to be regulated by the transcription factors Sp1 and NFY. We performed DNaseI hypersensitive assays and identified a hypersensitive site mapping closely upstream of exon 1 suggesting that chromatin remodeling may contribute to FPGS gene regulation. Using co-immunoprecipitation and Western blotting we investigated the role of histone modifications and chromatin remodeling on the expression of FPGS and uncovered interactions between NFY, Sp1 and HDAC1. Our results demonstrate that HDAC1 complexes with NFY and Sp1 transcription factors in both B- and T-ALL cells. DNA affinity precipitation assay (DAPA) revealed that the HDAC1-NFY and HDAC1-Sp1 complex binds to the NFY and Sp1 binding sites in the FPGS promoter. These findings suggest that transcription of the FPGS gene may be regulated by acetylation of NFY and Sp1 factors and interaction with HDAC1, and/or chromatin remodeling. We then examined the effect of the histone deacetylase inhibitor (HDACi) sodium butyrate (NaBu) on the expression of FPGS and other folate-related genes. The level of FPGS, ATP-binding cassette subfamily C (ABCC1), ATP-binding cassette subfamily G (ABCG2), DHFR, γ-glutamyl hydrolase (GGH), solute carrier family 19/folate transporter (SLC19A1), and TS mRNA gene expression was determined by qRT-PCR in NALM6 (Bp-ALL), REH (Bp-ALL, t(12,21)/TEL-AML1), SupB15 (Bp-ALL, t(9,22)/BCR-ABL), and CCRF-CEM (T-ALL) cells treated with NaBu [2mM-5mM]. In all cell lines examined, treatment with NaBu induced 2- to 5-fold the level of FPGS and ABCC1 mRNA expression whereas the level of DHFR, SLC19A1, and TS mRNA expression was decreased. Expression of GGH and ABCG2 mRNAs was increased 2-fold in CCRF-CEM but remained unaltered in Bp-ALL NaBu treated cells. Promoters of butyrate-responsive genes have been shown to contain genetic elements such as Sp1/Sp3 binding sites which interact with HDAC1 to mediate the action of NaBu. On this basis, we hypothesized that pre-treatment of ALL cells with NaBu should lead to induction of FPGS expression and subsequently, higher synthesis of MTX-PG and enhanced MTX cytotoxicity in ALL cells. To test this hypothesis, CCRF-CEM, NALM6, REH, and SupB15 cells were treated sequentially with NaBu (24h) and MTX (4h), and assessed for cell viability. Treatment of NaBu and MTX increased cell death by ∼40% in NALM6, REH, and SupB15 Bp-cells, and ∼60% in CCRF-CCEM cells when compared to treatment with each drug alone. These data suggest that combination of HDACi and MTX may represent a novel therapeutic strategy for treatment of ALL. This strategy may be particularly useful to overcome MTX resistance in patients diagnosed with phenotypes that accumulate low levels of MTX-PGs and for patients after relapse.

The Level of Histone Deacetylase 7 in Pediatric ALL and Its Effect on Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5099-5099
Author(s):  
Bei Hou ◽  
Huyong Zheng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Altered Expression ◽  
Expression Levels ◽  
Pediatric All

Abstract Background Leukemia is the most common pediatric malignancy and a major cause of mortality and morbidity in children. Nearly 15,000 children are newly diagnosed with leukemia in China each year and among them, acute lymphoblastic leukemia (ALL) accounts for more than 75%. Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment . With increasing focus on precision medicine, HDACs have emerged as promising therapeutic target in pediatric ALL. Methods We detect the histone deacetylase 7(HDAC7) expression in the bone marrow samples of 254 children with newly diagnosed acute lymphoblastic leukemia (ALL) at Hematology Oncology Center of Beijing Children`s Hospital from January 2010 to the end of 2012 via qRT-PCR using the TaqMan gene expression probes. 3 patients that have been completely remission for 3 years are used as normal control. We find out that the expression levels of HDAC7 are associated with the unfavorable events (such as induction failure, relapse and/or death due to any cause ) occurence rates and 5-EFS. Results Here we find that the HDAC7 expression levels are associated with the unfavorable events occurence rates and 5-EFS. We find that in the intermediate risk group of 157 patients, the patients who have lower level of HDAC7 expression have higher unfavorable event occurence rates than the higher expression of HDAC7 group (p=0.001). The group of higher HDAC7 expression have higher 5-EFS than the lower group in both the intermediate risk group(p=0.001) and the T-ALL group(n=18). Conclusion We conclude that HDAC7 has a potent anti-oncogenic effect on specific pediatric B-cell leukemia, indicating that its deregulation may contribute to the pathogenesis of the disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia

Blood ◽  
2010 ◽  
Vol 115 (9) ◽  
pp. 1735-1745 ◽  
Author(s):  
Takaomi Sanda ◽  
Xiaoyu Li ◽  
Alejandro Gutierrez ◽  
Yebin Ahn ◽  
Donna S. Neuberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Lymphoblastic Leukemia ◽  
Proteasome Inhibitors ◽  
Heat Shock Protein 90 ◽  
Cell Acute Lymphoblastic Leukemia

Abstract To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for γ-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-κB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.

Sign in / Sign up

Export Citation Format

Share Document