Decitabine in the treatment of acute myeloid leukemia in elderly patients

Malik, Priya; Cashen, Amanda F.

doi:10.2147/cmar.s40600

Cited by 48 publications

(29 citation statements)

References 50 publications

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“…These data indicate that restoration of SOX17 expression in CCA with demethylating agents could have important therapeutic value. Decitabine was reported to inhibit CCA cell growth in vitro and in a mouse xenograft model [29] and is a drug approved by the food and drug administration (FDA) for the treatment of human diseases such as myelodysplastic syndromes [30]. So, decitabine could be a drug to be considered for CCA.…”

Section: Discussionmentioning

confidence: 99%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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Background & aims Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. Methods SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knock-down were used. Gene expression and DNA methylation profiling were performed. Results SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knock-down in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17. Conclusions SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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“…The only currently FDA-approved DNA methylation inhibitors, 5-aza-2′-deoxycytidine and 5-azacytidine, are effective treatments for acute myeloid leukemia, yet typically responses are transient (Malik et al, 2014). Both agents broadly and non-specifically inhibit the DNMTs and result in significant DNA damage (Palii et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Acute Depletion Redefines the Division of Labor among DNA Methyltransferases in Methylating the Human Genome

et al. 2014

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Summary Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depletion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous.

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“…7 However, response rates are low. Combined rates of complete remission (complete remission with recovery of peripheral-blood counts) and complete remission with incomplete count recovery typically range from 20 to 35%.…”

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confidence: 99%

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Welch¹,

et al. 2016

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BACKGROUND The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine.

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Decitabine in the treatment of acute myeloid leukemia in elderly patients

Cited by 48 publications

References 50 publications

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Acute Depletion Redefines the Division of Labor among DNA Methyltransferases in Methylating the Human Genome

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes

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