1,348 research outputs found
Anti-Leukemia Activity of MS-275 Histone Deacetylase Inhibitor Implicates 4-1BBL/4-1BB Immunomodulatory Functions
Histone deacetylase inhibitors (HDACi) have demonstrated promising therapeutic potential in clinical trials for hematological malignancies. HDACi, such as SAHA/Vorinostat, Trichostatin A, and MS-275 were found to induce apoptosis of leukemic blasts through activation of the death receptor pathway and transcriptional induction of the Tumor Necrosis Factor (TNF)-related pro-apoptotic family members, TRAIL and FasL. The impact of HDACi on TNF-related costimulatory molecules such as 4-1BB ligand (4-1BBL/TNFSF9) is however not known. Following exposure to SAHA/Vorinostat, Trichostatin A, and MS-275, transcript levels were determined by real time PCR in Jurkat, Raji and U937 cells. Treatment with HDACi up-regulated TNFSF9 gene expression in the three leukemia cell lines, yet to different extend and with distinct kinetics, which did not require de novo protein synthesis and was not associated with DNAse I hypersensitive chromatin remodeling. Transcriptional activity of TNFSF9 promoter-luciferase constructs was induced up to 12 fold by HDACi, and implication of Sp1/Sp3 transcription factors binding to functional GC-box elements was evidenced by reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays. Functionality of modulated target genes was assessed in allogeneic mixed leukocyte reaction experiments. MS-275- and to a lesser extent Trichostatin A- and SAHA-treated Raji cells significantly up regulated T lymphocytes proliferation which was reduced by about 50% by a 4-1BB blocking recombinant protein, while MS-275- but neither Trichostatin A- nor SAHA-treated cells up-regulated IFNÎł secretion by T lymphocytes. Our results identify 4-1BBL/4-1BB as a downstream target of HDACi, especially of MS-275 anti-leukemia action in vitro. Thus, HDACi such as MS-275 displaying dual TNF-dependent proapoptotic and costimulatory activities might be favored for inclusion in HDACi-based anti-cancer therapeutic strategies
HDAC3 is essential for Human Leukemic Cell Growth and the Expression of ÎČ-catenin, MYC, and WT1
Therapy of acute myeloid leukemia (AML) is unsatisfactory. Histone deacetylase inhibitors (HDACi) are active against leukemic cells in vitro and in vivo. Clinical data suggest further testing of such epigenetic drugs and to identify mechanisms and markers for their efficacy. Primary and permanent AML cells were screened for viability, replication stress/DNA damage, and regrowth capacities after single exposures to the clinically used pan-HDACi panobinostat (LBH589), the class I HDACi entinostat/romidepsin (MS-275/FK228), the HDAC3 inhibitor RGFP966, the HDAC6 inhibitor marbostat-100, the non-steroidal anti-inflammatory drug (NSAID) indomethacin, and the replication stress inducer hydroxyurea (HU). Immunoblotting was used to test if HDACi modulate the leukemia-associated transcription factors beta-catenin, Wilms tumor (WT1), and myelocytomatosis oncogene (MYC). RNAi was used to delineate how these factors interact. We show that LBH589, MS-275, FK228, RGFP966, and HU induce apoptosis, replication stress/DNA damage, and apoptotic fragmentation of beta-catenin. Indomethacin destabilizes beta-catenin and potentiates anti-proliferative effects of HDACi. HDACi attenuate WT1 and MYC caspase-dependently and -independently. Genetic experiments reveal a cross-regulation between MYC and WT1 and a regulation of beta-catenin by WT1. In conclusion, reduced levels of beta-catenin, MYC, and WT1 are molecular markers for the efficacy of HDACi. HDAC3 inhibition induces apoptosis and disrupts tumor-associated protein expression
MS-275 (Entinostat) Promotes Radio-sensitivity in PAX3-FOXO1 Rhabdomyosarcoma cells
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% of RMS expresses fusion oncoproteins such as PAX3/PAX7âFOXO1 (fusionâpositive, FP) while fusionânegative (FN)âRMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local
control but metastatic RMS is often radioâresistant. HDAC inhibitors (HDACi) radioâsensitize different cancer cells types. Thus, we evaluated MSâ275 (Entinostat), a Class I and IV HDACi, in combination with RT on RMS cells in vitro and in vivo. MSâ275 reversibly hampered cell survival
in vitro in FNâRMS RD (RASmut) and irreversibly in FPâRMS RH30 cell lines downâregulating cyclin A, B, and D1, upâregulating p21 and p27 and reducing ERKs activity, and câMyc expression in RD and PI3K/Akt/mTOR activity and NâMyc expression in RH30 cells. Further, MSâ275 and RT
combination reduced colony formation ability of RH30 cells. In both cell lines, coâtreatment increased DNA damage repair inhibition and reactive oxygen species formation, downâregulated NRF2, SOD, CAT and GPx4 antiâoxidant genes and improved RT ability to induce G2 growth arrest.
MSâ275 inhibited in vivo growth of RH30 cells and completely prevented the growth of RTâunresponsive RH30 xenografts when combined with radiation. Thus, MSâ275 could be considered as a radioâsensitizing agent for the treatment of intrinsically radioâresistant PAX3âFOXO1 RMS
Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
The clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ progenitor cells with two chemically distinct HDACi inhibitors MS-275 or SAHA and analyzed their effects on the transcriptome (RNA-seq), epigenome (H3K27ac ChIP-seq) and functional and morphological characteristics during neutrophil development. MS-275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1, while SAHA (vorinostat) is a non-selective class I/II HDACi. Treatment with individual HDACi resulted in both overlapping and distinct effects on both transcriptome and epigenome, whereas functional effects were relatively similar. Both HDACi resulted in reduced expansion and increased apoptosis in neutrophil progenitor cells. Morphologically, HDACi disrupted normal neutrophil differentiation what was illustrated by decreased percentages of mature neutrophils. In addition, while SAHA treatment clearly showed a block at the promyelocytic stage, MS-275 treatment was characterized by dysplastic features and skewing towards the monocytic lineage. These effects could be mimicked using shRNA-mediated knockdown of HDAC1. Taken together, our data provide novel insights into the effects of HDAC inhibition on normal hematopoietic cells during neutrophil differentiation. These findings should be taken into account when considering the clinical use of MS-275 and SAHA, and can be potentially utilized to tailor more specific, hematopoietic-directed HDACi in the future
The effect of histone deacetylase inhibitors on SRC and BCL2L1 gene expression and a potential role for phosphatases in their transcriptional repression
Histone Deacetylase Inhibitors (HDACi) are a new class of chemotherapeutics which have shown promise in pre-clinical and clinical settings. HDACi have been shown to act by re-programming gene expression, with the transcription of some genes such as p21WAF1 being activated, while others like SRC and BCL2L1 are repressed. The mechanism behind HDACi gene expression changes remains unknown; although it has been shown to involve a direct interaction with gene promoters.
Using a quantitative qRT-PCR approach, the effect of various HDACi on the transcription of p21WAF1, SRC and BCL2L1 was examined. TSA and apicidin led to an up regulation of p21WAF1 mRNA levels while c-Src and Bcl-xL mRNA levels were downregulated. Short c-Src mRNA transcripts were unaffected following TSA and apicidin treatments, despite the full length transcripts being repressed. Repression of full length c-Src and Bcl-xL mRNA transcripts was not seen following treatment with MS-275 and MGCD0103, although p21WAF1 mRNA expression was induced. ChIP experiments revealed that following HDACi treatment, histone acetylation levels and RNA Polymerase II occupancy increased in the promoter regions of both the SRC and BCL2L1 genes. RNA Polymerase II occupancy lasted less than 15 minutes in the 3â regions of the gene following treatment with apicidin and TSA, but was more long-term following MS-275 and MGCD0103 treatment. The protein phosphatase inhibitor Calyculin A completely blocked HDACi mediated repression of c-Src and Bcl-xL mRNA, suggesting a role for protein phosphatases in the mechanism behind HDACi.
It is therefore hypothesized that HDACi work through at least two different mechanisms. Whether or not an HDACi leads to gene repression depends on its ability to disrupt an HDAC/protein phosphatase complex and not on their HDAC specificities. The disruption of the complex leads to the release of an active protein phosphatase. The released phosphatase can then presumably act on various factors changing a gene from an active to paused state, possibly through promoter proximal pausing. HDACi unable to disrupt this complex are unable to induce gene repression. Collectively, these studies highlight not only the complexity of HDACi mediated effects within the cell, but also present a new explanation behind HDACi mediated gene repression
Histone Deacetylase Inhibitors Globally Enhance H3/H4 Tail Acetylation Without Affecting H3 Lysine 56 Acetylation
Histone deacetylase inhibitors (HDACi) represent a promising avenue for cancer therapy. We applied mass spectrometry (MS) to determine the impact of clinically relevant HDACi on global levels of histone acetylation. Intact histone profiling revealed that the HDACi SAHA and MS-275 globally increased histone H3 and H4 acetylation in both normal diploid fibroblasts and transformed human cells. Histone H3 lysine 56 acetylation (H3K56ac) recently elicited much interest and controversy due to its potential as a diagnostic and prognostic marker for a broad diversity of cancers. Using quantitative MS, we demonstrate that H3K56ac is much less abundant than previously reported in human cells. Unexpectedly, in contrast to H3/H4 N-terminal tail acetylation, H3K56ac did not increase in response to inhibitors of each class of HDACs. In addition, we demonstrate that antibodies raised against H3K56ac peptides cross-react against H3 N-terminal tail acetylation sites that carry sequence similarity to residues flanking H3K56
Die Wirkung des Sirtuininhibitors Tenovin-1 im Vergleich zu den Histondeacetylaseinhibitoren SAHA und MS-275 auf den RETRA-induzierten Zelltod in p53-mutierten, -Null und -Wildtyp Ewing-Sarkom-Zellen
Das Ewing-Sarkom ist der zweithĂ€ufigste primĂ€re Knochentumor im Kindesalter (Balamuth und Womer 2010). Zwar konnte in den letzten Jahrzehnten dank verbesserter Therapiemöglichkeiten das progressionsfreie Ăberleben erhöht werden, jedoch weist eine metastasierte Erkrankung immer noch eine schlechte Prognose und ein Ăberleben von maximal 30 % auf (Cotterill et al. 2000). Die in diesem Zusammenhang durchgefĂŒhrte Forschungsarbeit untersuchte die antineoplastischen Effekte der Behandlung der Histondeacetylase-Inhibitoren (HDACi) SAHA und MS-275 bzw. des Sirtuininhibitors (SIRTi) Tenovin-1 in Kombination mit dem p73-Aktivator RETRA in Ewing-Sarkom-Zellen mit unterschiedlichem p53-Status. RETRA ist ein neuer niedermolekularer Wirkstoff, der die Interaktion zwischen dem mutierten Tumorsuppressorprotein p53 und p73 inhibiert, wodurch das freie p73 seine TumorsuppressoraktivitĂ€t entfalten kann (Kravchenko et al. 2008). Zur Untersuchung des Zelltodes wurden zytometrische Analysen, wie die Propidiumjodid-Aufnahme, die Messung des mitochondrialen Membranpotenzials sowie der Caspase-3-AktivitĂ€tstest verwendet. Sowohl in mutierten, Null- und Wildtyp-p53-Zellen konnte durch die Behandlung von RETRA der Zelltod induziert werden. Dieser zytotoxische Effekt konnte in allen Zelllinien durch die jeweilige Applikation mit den HDACi SAHA und MS-275 deutlich gesteigert werden. Hingegen wurde durch die Zugabe des SIRTi Tenovin-1 eine AbschwĂ€chung der ZytotoxizitĂ€t von RETRA in allen Zelllinien beobachtet. Des Weiteren sollten Genexpressionsanalysen des p21, eines Zielgens von p53, einen Aufschluss ĂŒber den Wirkungsmechanismus der verwendeten Substanzen geben. In meiner Promotion konnte die VerstĂ€rkung des RETRA-induzierten Zelltodes durch die Zugabe der HDACi SAHA und MS-275 unabhĂ€ngig vom p53-Status nachgewiesen werden. Im Vergleich dazu fand durch den Sirtuininhibitor Tenovin-1 eine Abnahme des RETRA-induzierten Zelltodes statt, was eine mögliche tumorsuppressive Funktion der Sirtuine in Ewing-Sarkom-Zellen vermuten lĂ€sst. Diese Ergebnisse zeigen die mögliche Verwendung der HDACi SAHA und MS-275, nicht aber Tenovin-1, in Kombination mit RETRA als neue erfolgsversprechende Antitumortherapie des Ewing-Sarkoms auf
Wirkung der Klasse I spezifischen Histondeacetylaseinhibitoren MS-275 und MGCD0103 sowie des Breitspektruminhibitors LBH589 auf die Differenzierung von humanen mesenchymalen Stammzellen
Die Transplantation von insulinproduzierenden Zellen, die aus körpereigenen Stammzellen gewonnen werden stellt einen experimentellen Ansatz zur Therapie des Diabetes mellitus Typ 1 dar.
In einer Reihe von Differenzierungsprotokollen werden Histondeacetylaseinhibitoren (HDACi) genutzt, um die Wirkung von differenzierungsrelevanten Faktoren mittels epigenetischer Modifikationen zu verstĂ€rken. HDACi fĂŒhren u.a. durch VerstĂ€rkung acetylierter Histonmodifikationen zu gelockertem Chromatin und somit zu erhöhter Genexpression unterschiedlicher Gene. Sie können dadurch Einfluss auf die Differenzierung von Stammzellen nehmen und kontrollieren eine Vielzahl verschiedener DifferenzierungsvorgĂ€nge. Wir untersuchten die isolierte Wirkung dieser HDACi auf humane, mesenchymale Stammzellen. Hierzu fĂŒhrten wir eine Zellkultur ĂŒber fĂŒnf Tage durch und behandelten die Zellen mit einem Breitspektruminhibitor (LBH589), sowie mit den Klasse-I-spezifischen HDACi MS-275 und MGCD0103.
Zu definierten Zeitpunkten wurde die Genexpression des insulin gene enhancer protein (ISL-1) und des paired-box-gene 6 (Pax6) gemessen, zwei Transkriptionsfaktoren, die eine Rolle bei der Embryogenese des Pankreas spielen.
In den mit LBH589 behandelten Zellen zeigte sich eine signifikante Erhöhung der Genexpression dieser Gene in dynamischem Muster. Die Klasse-I-spezifischen HDACi zeigten hingegen keine signifikante Beeinflussung der untersuchten Gene.
Alle drei HDACi hatten einen antiproliferativen Effekt auf eine Telomerase- immortalisierte Stammzelllinie. LBH589 ist ein klinisch etablierter HDACi im Bereich hĂ€mato-onkolgischer Neoplasien. Er wirkt antiproliferativ, induziert Differenzierung und fĂŒhrt zur Apoptose von Tumorzellen. Dies könnte helfen dem aktuell bestehenden Problem einer Tumorformation nach Transplantation zu entgegnen.
LBH589 als Breitspektruminhibitor prĂ€sentiert somit zwei wichtige Eigenschaften, die ihn fĂŒr weitere EinsĂ€tze in Differenzierungsprotokollen attraktiv erscheinen lassen.The application of insulin producing cells, which are obtained from autologous mesenchymal stem cells represents an experimental approach for the treatment of typ I diabetes.
There are several differentiation protocols in which Histondeacetylase- Inhibitors (HDACi) are used to enhance the effect of transcription factors by modifying epigenetic signals.
They inhibit HDACs and thereby lead to prevention of condense DNA structure, following activation of gene transcription.
Panobinostat (LBH-589) is a broad spectrum Inhibitor, which inhibits HDACs of class I as well as class II and IV. Entinostat (MS-275) and Mocetinostat (MGCD0103) are specific for class I HDACs.
To analyze the effect of histon-deacetylase inhibition on human mesenchymal stem cells, we performed cell culture for five days, using the braodspectrum HDACi LBH589 as well as the class-I-specific HDACi MS-275 and MGCD0103.
After 6h, 24h, 48h and 120h we measured the expression of insulin gene enhancer protein (ISL-1) and paired-box-gene 6 (Pax6), two markers for Langerhans-cell development, by using real-time PCR.
We found that HDAC inhibition by LBH589 upregulates the expression of these genes in a significant way, whereas MS-275 and MGCD0103 did not show any significant changes in gene expression.
Furthermore all of the three HDACi showed an antiproliferative effect on telomerase immortalized stem cells. LBH589 has already proved its anticancer acitvity in clinical use.
This feature might offer the possibility to prevent tumor formation after transplantation of differentiated stem cells in vivo.
Taken together, LBH589 as a broadspectrum HDACi offers the opportunity to be used as a component in further differentiation protocosl to suppport differentiation as well as to prevent tumor formation
Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer
Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the nonspecific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets. Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription. Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies
Regulation von Apoptose, Autophagie und DNA-IntegritÀt in LeukÀmiezellen durch replikativen Stress und pharmakologische Hemmung der Histondeacetylasen
Die chronische myeloische LeukĂ€mie (CML) ist eine Krebserkrankung, die durch das onkogene BCR/ABL Fusionsprotein charakterisiert ist. Die zielgerichtete Therapie mit Tyrosinkinase-Inhibitoren ermöglicht in bis zu 80% der FĂ€lle eine normale Lebenserwartung. Allerdings bleiben leukĂ€mische Stammzellen meist erhalten und können zu einer Neuerkrankung fĂŒhren. Derzeit werden Histondeacetylase-Inhibitoren (HDACi) entwickelt, die als vielversprechende Krebsmedikamente in der Therapie von hĂ€matologischen Erkrankungen eingesetzt werden. Dabei sind Kombinationstherapien mit Chemotherapeutika im Fokus, da sie effizienter als Monotherapien sind. Hydroxyurea wird aktuell als stabiles Medikament gegen SichelzellanĂ€mie sowie gegen chronische myeloproliferative Erkrankungen eingesetzt. Aufgrund der Funktion als Ribonukleotidreduktase-Inhibitor wird Hydroxyurea in Laboren oft dazu verwendet, gezielt replikativen Stress durch Depletion von dNTPs zu induzieren. Replikativer Stress setzt in den Zellen eine komplexe Zellantwort in Gang. Dabei spielen Prozesse wie die DNA-Schadensantwort, Apoptose und Autophagie eine wichtige Rolle. In dieser Arbeit wurde untersucht, ob der Klasse I HDACi MS 275 CML Zellen gegenĂŒber Hydroxyurea sensitiviert. Die Daten zeigen, dass MS 275 die Expression des CDKi p21 und einen G1 Arrest der Zellen auslöst. Hydroxyurea hingegen arretiert die Zellen in der S Phase und fördert die Autophagie. Die kombinierte Gabe von MS 275 und Hydroxyurea fĂŒhrt zu einer signifikanten und synergistischen Zunahme der Apoptose, sowie zu einer Caspase abhĂ€ngigen Proteolyse von Autophagieregulatoren. Als kritischen Faktor fĂŒr eine von dem Tumorsuppressor p53-unabhĂ€ngige Apoptoseinduktion wurde das pro apoptotische Protein NOXA ermittelt. Experimente mit einer genetischen Eliminierung von NOXA sowie Versuche mit NOXA-defizienten MEFs belegen eine unabdingbare Rolle von NOXA in der Aktivierung der Apoptosekaskade nach Kombinationsbehandlung in CML Zellen. Als weitere wichtige Faktoren des Apoptosewegs wurden c-ABL und p73 als vorgeschaltete Regulatoren von NOXA ausfindig gemacht. Die Untersuchung der DNA Schadensantwort ergab, dass MS 275 die von Hydroxyurea induzierte Aktivierung von Checkpoint-Kinasen, sowie insbesondere die Mengen an DNA StrangbrĂŒchen deutlich erhöht. Die pharmakologische Hemmung von ATR und CHK1 hat eine zusĂ€tzliche Zunahme an DNA SchĂ€den in MS-275/Hydroxyurea behandelten CML Zellen zur Folge. Die Inaktivierung der ATR-CHK1 Achse fĂŒhrt zu einer signifikanten Reduktion der durch MS-275/Hydroxyurea induzierten Apoptose. Diese Daten legen eine bisher unbekannte pro-apoptotische Rolle von ATR und CHK1 durch eine transkriptionelle Regulation von NOXA offen. Zudem wird dargelegt, dass Klasse I HDACs unerlĂ€sslich fĂŒr die DNA-Reparatur, die Hemmung der Apoptose sowie fĂŒr den Erhalt der Autophagie in CML Zellen nach replikativem Stress sind. Der aufgedeckte Mechanismus kann als generelles Konzept fĂŒr die Wirkungsweise von Hydroxyurea und HDACi, insbesondere im Kontext der CML verstanden werden. Da die Behandlungsstrategie mit Hydroxyurea und HDACi vielversprechende Daten liefert, ermutigt dies zu Analysen der Kombinationstherapie in klinischen Studien.Chronic myeloid leukemia (CML) is a hematological disorder characterized by the presence of the oncogenic fusion protein BCR/ABL. The targeted therapy with tyrosine kinase inhibitors allows in up to 80% of all CML cases an ordinary life expectancy. However, remaining leukemic stem cells can lead to new cases. At present, histone deacetylase inhibitors (HDACi) are newly developed and used as promising cancer drugs in therapy of leukemia. Combination therapies of chemotherapeutics are gaining in importance more and more, as they show higher efficacies than monotherapies. Hydroxyurea is currently the stable drug for the treatment of sickle cell anemia and chronic myeloproliferative disorders. As hydroxyurea acts as a ribonucleotide reductase inhibitor, it is commonly used in laboratories for generating replicative stress through depletion of the dNTP pool. Replicative Stress induces a complex cellular program involving DNA damage response, apoptosis and autophagy. In this thesis, I analysed if the class I HDACi MS-275 sensitizes CML cells towards hydroxyurea. Here I show that MS-275 induces the expression of the CDKi p21 and stalls the cells in G1 phase. Whereas hydroxyurea arrests the cells in S phase and triggers autophagy. The additional application of MS-275 leads to a significant and synergistic increase in apoptosis as well as to a caspase-dependent cleavage of autophagic regulators. As critical factor in inducing p53-independent apoptosis the pro-apoptotic protein NOXA was determined. Genetic elimination of NOXA as well as experiments with NOXA deficient MEFs confirmed the important role of this protein in activation of the apoptotic cascade upon MS-275/Hydroxyurea treatment in CML cells. As further critical factors in the apoptotic pathway c-ABL and p73 were found as upstream regulators of NOXA. The investigation of the DNA damage response revealed that the class I HDACi MS 275 enhances the hydroxyurea-induced activation of checkpoint kinases as well as the amount of DNA strand breaks, notably. The pharmacological inhibition of ATR and CHK1 results in a distinct accumulation of DNA damage in MS-275/Hydroxyurea-treated CML cells. The inactivation of the ATR-CHK1 axis evokes a significant reduction of the MS 275/Hydroxyurea induced apoptosis. My data reveal a previously unidentified pro-apoptotic role of ATR and CHK1 through a transcriptional control of NOXA. Furthermore, I demonstrate that class I HDACs are necessary to initiate DNA repair, to prevent apoptosis and to sustain autophagy during replicative stress in CML cells. The disclosed mechanism is to be taken as a concept for the efficacy of hydroxyurea and HDACi especially in the context of CML. As the therapeutic strategy of hydroxyurea and HDACi show promising results, this encourages one to introduce the combinatorial therapy in clinical trials
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