The Experts below are selected from a list of 15018 Experts worldwide ranked by ideXlab platform
Vinothkumar Rajan - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of nup98 hoxa9 induced myeloid disease
Leukemia, 2015Co-Authors: Adam P Deveau, A M Forrester, Andrew J Coombs, G S Wagner, Clemens Grabher, I C Chute, Daniel Leger, Matthew Mingay, Gabriela Alexe, Vinothkumar RajanAbstract:Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of NUP98–HOXA9 -induced myeloid disease
-
Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of nup98 hoxa9 induced myeloid disease
Leukemia, 2015Co-Authors: Adam P Deveau, A M Forrester, G S Wagner, Clemens Grabher, I C Chute, Daniel Leger, Matthew Mingay, Gabriela Alexe, Andrew Coombs, Vinothkumar RajanAbstract:Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98–HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5)-methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds.
Michael J Topper - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Therapy inhibits metastases by disrupting premetastatic niches
Nature, 2020Co-Authors: Jianling Zou, Michael J Topper, Yong Tao, Hao Zhang, Xi Jiao, Wenbing Xie, Xiangqian Kong, Michelle Vaz, Yi Cai, Limin XiaAbstract:Cancer recurrence after surgery remains an unresolved clinical problem1–3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4–6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant Epigenetic Therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant Epigenetic Therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemoTherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant Epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer Therapy. In mouse models of pulmonary metastasis, adjuvant Epigenetic Therapy targeting myeloid-derived suppressor cells disrupts the premetastatic microenvironment after resection of primary tumours and inhibits the dissemination of residual tumour cells.
-
Epigenetic Therapy inhibits metastases by disrupting premetastatic niches
Nature, 2020Co-Authors: Jianling Zou, Michael J Topper, Yong Tao, Hao Zhang, Xi Jiao, Wenbing Xie, Xiangqian Kong, Michelle Vaz, Yi Cai, Limin XiaAbstract:Cancer recurrence after surgery remains an unresolved clinical problem1-3. Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites4-6. There are currently no effective interventions that prevent the formation of the premetastatic microenvironment6,7. Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant Epigenetic Therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant Epigenetic Therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemoTherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant Epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer Therapy.
-
Epigenetic Therapy activates type i interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Meredith L Stone, Michael J Topper, Katherine B. Chiappinelli, Lauren Murphy, Meghan Travers, Dimitrios Mathios, Michael Lim, Ie Ming Shih, Tianli Wang, Chien Fu HungAbstract:Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint Therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.
-
Epigenetic Therapy ties myc depletion to reversing immune evasion and treating lung cancer
Cell, 2017Co-Authors: Michael J Topper, Michelle Vaz, Katherine B. Chiappinelli, Christina Destefano E Shields, Noushin Niknafs, Ray Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew BallewAbstract:Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune Therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint Therapy for NSCLC.
Stephen B Baylin - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Therapy for epithelioid sarcoma
Cell, 2020Co-Authors: Scott B Rothbart, Stephen B BaylinAbstract:Tazemetostat is the first Epigenetic Therapy to gain FDA approval in a solid tumor. This lysine methyltransferase inhibitor targets EZH2, the enzymatic subunit of the PRC2 transcriptional silencing complex. Tumors with mutations in subunits of the SWI/SNF chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to EZH2 inhibition.
-
abstract ia12 Epigenetic Therapy potential efficacy for enhancing immune checkpoint Therapy
Cancer immunology research, 2020Co-Authors: Stephen B BaylinAbstract:Despite the tremendous contribution made to date by immune checkpoint Therapy to cancer management, most patients with the most common and deadliest forms of advanced cancer still do not receive durable benefit. Achieving manifest responses initially, understanding what predicts and contributes to long-term overall survival, and how to reverse initial or evolved resistance are all still major challenges to be addressed. Developing combinatorial approaches that may contribute to all of the above issues is a major goal, and Epigenetic Therapy is in play as one strategy for this purpose. Key specific points of the overall potential for the merits of combining this latter approach with immune checkpoint and other immunotherapies will be discussed in this presentation and include: 1) Critical steps in tumor immune evasion are under Epigenetic control and can be reversed experimentally. There is evidence emerging that this also may be accomplished in patients and with Epigenetic Therapy drugs clinically available and in clinical trials such as DNA methyltransferase (DNMTis) and histone deactylase inhibitors (HDACis). The above steps for these drugs include restoration of tumor antigen presentation processes, restoration of tumor cell signaling for attraction of key antitumor subsets of immune cells, repulsion from tumors of key cells that promote immune tolerance, and repression of key oncogenic signaling pathways that otherwise suppress these above tumor immune attraction signals. 2) Key facets of immune tolerance inherent to signaling in immune cell subsets are under the control of Epigenetic processes, and these too can be reversed by the types of drugs listed above, including T-cell and other immune cell exhaustion signaling, behavior of key ligands and receptors on immune cells critical for their migration to tumor cell sites and attack of cancer cells. Key experimental data for the above processes, coming from our own lab group and many collaborations within our participation in the Van Andel Institute – Stand Up To Cancer (VAI-SU2C) Epigenetic Therapy dream team, will be presented to support the hypotheses articulated above. Barriers to achieving efficacy of the approach, including which drugs will ultimately prevail, how to best sequence administration of the drugs, what cancer stages are most optimal for Therapy institution, and what molecular parameters are promising for predicting efficacy, will also be discussed. Citation Format: Stephen B. Baylin. Epigenetic Therapy—potential efficacy for enhancing immune checkpoint Therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and ImmunoTherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA12.
-
inhibiting dna methylation activates cancer testis antigens and expression of the antigen processing and presentation machinery in colon and ovarian cancer cells
PLOS ONE, 2017Co-Authors: Cornelia Siebenkas, Stephen B Baylin, Anup Sharma, Katherine Kb Chiappinelli, Angela A Guzzetta, Jana Jeschke, Rajita Vatapalli, Nita AhujaAbstract:: Innovative therapies for solid tumors are urgently needed. Recently, therapies that harness the host immune system to fight cancer cells have successfully treated a subset of patients with solid tumors. These responses have been strong and durable but observed in subsets of patients. Work from our group and others has shown that Epigenetic Therapy, specifically inhibiting the silencing DNA methylation mark, activates immune signaling in tumor cells and can sensitize to immune Therapy in murine models. Here we show that colon and ovarian cancer cell lines exhibit lower expression of transcripts involved in antigen processing and presentation to immune cells compared to normal tissues. In addition, treatment with clinically relevant low doses of DNMT inhibitors (that remove DNA methylation) increases expression of both antigen processing and presentation and Cancer Testis Antigens in these cell lines. We confirm that treatment with DNMT inhibitors upregulates expression of the antigen processing and presentation molecules B2M, CALR, CD58, PSMB8, PSMB9 at the RNA and protein level in a wider range of colon and ovarian cancer cell lines and treatment time points than had been described previously. In addition, we show that DNMTi treatment upregulates many Cancer Testis Antigens common to both colon and ovarian cancer. This increase of both antigens and antigen presentation by Epigenetic Therapy may be one mechanism to sensitize patients to immune therapies.
-
Epigenetic Therapy for solid tumors from bench science to clinical trials
Epigenomics, 2015Co-Authors: Yenyi Juo, Stephen B Baylin, Nilofer S Azad, Xue Jun Gong, Ankita Mishra, Xiao Cui, Nita AhujaAbstract:The cancer epigenome is characterized by global DNA methylation and chromatin changes, such as the hypermethylation of specific CpG island promoters. Epigenetic agents like DNA methyltransferase or histone deacetylase inhibitors induce phenotype changes by reactivation of Epigenetically silenced tumor suppressor genes. Despite initial promise in hematologic malignancies, Epigenetic agents have not shown significant efficacy as monoTherapy against solid tumors. Recent trials showed that Epigenetic agents exert favorable modifier effects when combined with chemoTherapy, hormonal Therapy, or other Epigenetic agents. Due to the novel nature of their mechanism, it is important to reconsider the optimal patient selection, drug regimen, study design, and outcome measures when pursuing future trials in order to discover the full potential of this new therapeutic modality.
-
harnessing the potential of Epigenetic Therapy to target solid tumors
Journal of Clinical Investigation, 2014Co-Authors: Nita Ahuja, Hariharan Easwaran, Stephen B BaylinAbstract:Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of Epigenetic therapies for cancer.
Peter A Jones - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Therapy in immune oncology
Nature Reviews Cancer, 2019Co-Authors: Peter A Jones, Ankur Chakravarthy, Hitoshi Ohtani, Daniel D De CarvalhoAbstract:DNA methylation inhibitors have become the mainstay for treatment of certain haematological malignancies. In addition to their abilities to reactivate genes, including tumour suppressors, that have acquired DNA methylation during carcinogenesis, they induce the expression of thousands of transposable elements including endogenous retroviruses and latent cancer testis antigens normally silenced by DNA methylation in most somatic cells. This results in a state of viral mimicry in which treated cells mount an innate immune response by turning on viral defence genes and potentially expressing neoantigens. Furthermore, these changes mediated by DNA methylation inhibitors can also alter the function of immune cells relevant to acquired immunity. Additionally, other inhibitors of Epigenetic processes, such as histone deacetylases, methylases and demethylases, can elicit similar effects either individually or in combinations with DNA methylation inhibitors. These findings together with rapid development of immunotherapies open new avenues for cancer treatment.
-
targeting dna methylation for Epigenetic Therapy
Trends in Pharmacological Sciences, 2010Co-Authors: Xiaojing Yang, Fides D Lay, Han Han, Peter A JonesAbstract:Patterns of DNA methylation are established during embryonic development and faithfully copied through somatic cell divisions. Based on current understanding of DNA methylation and other interrelated Epigenetic modifications, a comprehensive view of the 'Epigenetic landscape' and cancer epigenome is evolving. The cancer methylome is highly disrupted, making DNA methylation an excellent target for anticancer therapies. During the last few decades, an increasing number of drugs targeting DNA methylation have been developed to increase efficacy and stability and to decrease toxicity. The earliest and the most successful Epigenetic drug to date, 5-Azacytidine, is currently recommended as the first-line treatment of high-risk myelodysplastic syndromes (MDS). Encouraging results from clinical trials have prompted further efforts to elucidate Epigenetic alterations in cancer, and to subsequently develop new Epigenetic therapies. This review delineates the latest cancer Epigenetic models, the recent discovery of hypomethylation agents as well as their application in the clinic.
-
Long-term Epigenetic Therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice.
Cancer prevention research (Philadelphia Pa.), 2008Co-Authors: Christine B. Yoo, Victor E. Marquez, Allen S. Yang, Jody C. Chuang, Hyang-min Byun, Gerda Egger, Louis Dubeau, Tiffany I. Long, Peter W. Laird, Peter A JonesAbstract:Recent successes in the application of Epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone ApcMin/+ (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with Epigenetic drugs resulted in only minor developmental and histologic changes.
-
cancer Epigenetics modifications screening and Therapy
Annual Review of Medicine, 2008Co-Authors: Einav Nili Galyam, Yoshimasa Saito, Gerda Egger, Peter A JonesAbstract:Deregulation of gene expression is a hallmark of cancer. Although genetic lesions have been the focus of cancer research for many years, it has become increasingly recognized that aberrant Epigenetic modifications also play major roles in the tumorigenic process. These modifications are imposed on chromatin, do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable through many cell divisions. We review these modifications in normal and cancer cells and the evolving approaches used to study them. Additionally, we outline advances in their potential use for cancer diagnostics and targeted Epigenetic Therapy.
-
Epigenetic Therapy of cancer past present and future
Nature Reviews Drug Discovery, 2006Co-Authors: Christine B. Yoo, Peter A JonesAbstract:The initiation and progression of cancer is controlled by both genetic and Epigenetic events. Unlike genetic alterations, which are almost impossible to reverse, Epigenetic aberrations are potentially reversible, allowing the malignant cell population to revert to a more normal state. With the advent of numerous drugs that target specific enzymes involved in the Epigenetic regulation of gene expression, the utilization of Epigenetic targets is emerging as an effective and valuable approach to chemoTherapy as well as chemoprevention of cancer.
Adam P Deveau - One of the best experts on this subject based on the ideXlab platform.
-
Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of nup98 hoxa9 induced myeloid disease
Leukemia, 2015Co-Authors: Adam P Deveau, A M Forrester, Andrew J Coombs, G S Wagner, Clemens Grabher, I C Chute, Daniel Leger, Matthew Mingay, Gabriela Alexe, Vinothkumar RajanAbstract:Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of NUP98–HOXA9 -induced myeloid disease
-
Epigenetic Therapy restores normal hematopoiesis in a zebrafish model of nup98 hoxa9 induced myeloid disease
Leukemia, 2015Co-Authors: Adam P Deveau, A M Forrester, G S Wagner, Clemens Grabher, I C Chute, Daniel Leger, Matthew Mingay, Gabriela Alexe, Andrew Coombs, Vinothkumar RajanAbstract:Acute myeloid leukemia (AML) occurs when multiple genetic aberrations alter white blood cell development, leading to hyperproliferation and arrest of cell differentiation. Pertinent animal models link in vitro studies with the use of new agents in clinical trials. We generated a transgenic zebrafish expressing human NUP98–HOXA9 (NHA9), a fusion oncogene found in high-risk AML. Embryos developed a preleukemic state with anemia and myeloid cell expansion, and adult fish developed a myeloproliferative neoplasm (MPN). We leveraged this model to show that NHA9 increases the number of hematopoietic stem cells, and that oncogenic function of NHA9 depends on downstream activation of meis1, the PTGS/COX pathway and genome hypermethylation through the DNA methyltransferase, dnmt1. We restored normal hematopoiesis in NHA9 embryos with knockdown of meis1 or dnmt1, as well as pharmacologic treatment with DNA (cytosine-5)-methyltransferase (DNMT) inhibitors or cyclo-oxygenase (COX) inhibitors. DNMT inhibitors reduced genome methylation to near normal levels. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of a histone deacetylase inhibitor plus either a DNMT inhibitor or COX inhibitor to block the effects of NHA9 on zebrafish blood development. Our work proposes novel drug targets in NHA9-induced myeloid disease, and suggests rational therapies by combining minimal doses of known bioactive compounds.
-
preclinical determination of the efficacy of Epigenetic Therapy in high risk myeloid disease using the zebrafish model
Blood, 2014Co-Authors: Adam P Deveau, A M Forrester, Clemens Grabher, I C Chute, Daniel Leger, Matthew Mingay, Andrew Coombs, Gretchen Wagner, Stephen M Lewis, Martin HirstAbstract:Epigenetic Therapy implies the use of drugs that target regulators of gene expression, such as DNA and histone methylation or histone acetylation, without altering the DNA coding sequence. Epigenetic mechanisms have been found to be perturbed in myeloid diseases, and in fact, the DNA demethylating agents, 5-azacytadine and decitabine are FDA approved drugs for myelodysplastic syndrome. However, use of Epigenetic therapies in other types of myeloid disease including acute myeloid leukemia (AML) has been met with variable success, suggesting efficacy might be improved by preselecting subtypes of disease in which there is a high degree of Epigenetic dysregulation. AML has recently been found to be associated with a host of Epigenetic abnormalities including mutations in DNA methyltransferase 3A ( DNMT3A ), ten-eleven translocation-2 ( TET2 ) and enhancer of zeste homolog 2 ( EZH2 ). We generated a transgenic zebrafish model of high risk myeloid disease expressing the human NUP98-HOXA9 ( NHA9 ) fusion oncogene, a genetic lesion for which Epigenetic dysregulation has not previously been identified. Transgenic embryos exhibit an increase in immature myeloid cells at the expense of erythroid cells and adult fish develop a myeloproliferative neoplasm (MPN). Leveraging this model in a microarray screen, we identified 3-fold elevated levels of the Epigenetic regulator, dnmt1, the major maintenance methyltransferase, for the first time in high risk AML. Decitabine specifically inhibits DNMT1 and treatment of NHA9 transgenic embryos with 75µM decitabine restored normal hematopoiesis, as evidenced by normal numbers of leukocytes and red cells. Moreover, using hematopoietic stem cell (HSC) reporter lines and whole mount in situ hybridization, we identified a 2-3 fold increase in this population in NHA9 embryos, suggesting the HSC as the cell of origin in this disease. Interestingly, 75µM decitabine Therapy also restored normal HSC numbers. Strikingly, we discovered synergy when we combined sub-monotherapeutic doses of DNMT1 inhibitors, decitabine (10-25µM) or zebularine (100µM), plus histone deacetylase inhibitors, valproic acid (25-100µM) or trichostatin A (250nM), to inhibit the effects of NHA9 on hematopoiesis. To determine if NHA9 expression directly results in changes to DNA methylation, we performed MeDIP-Seq on genomic DNA from pools of untreated and decitabine-treated NHA9 or control embryos. Untreated NHA9 embryos displayed significantly higher methylation levels at the regions of gene promoters compared to control embryos, which were restored to control levels following treatment with 75µM decitabine. Similarly, combination Therapy with 10µM decitabine and 25µM valproic acid significantly reduced methylation to near control levels following a 5 hour treatment, while prolonged exposures to these same doses resulted in profound global hypomethylation. These findings elucidate underlying mechanisms in the pathogenesis of NHA9 -induced myeloid disease and propose novel actionable Epigenetic drug targets. Furthermore, we highlight the opportunities inherent in the zebrafish model as a unique in vivo platform for the preclinical screening of Epigenetic based combination Therapy. Disclosures No relevant conflicts of interest to declare.