Correction: Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes.
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ABSTRACT:
SUBMITTER: Cedena MT
PROVIDER: S-EPMC6089387 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
Correction: Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes.
Cedena M Teresa MT Rapado Inmaculada I Santos-Lozano Alejandro A Ayala Rosa R Onecha Esther E Abaigar María M Such Esperanza E Ramos Fernando F Cervera José J Díez-Campelo María M Sanz Guillermo G Rivas Jesús Hernández JH Lucía Alejandro A Martínez-López Joaquin J
Oncotarget 20180720 56
[This corrects the article DOI: 10.18632/oncotarget.22157.]. ...[more]
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Project description:We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ?1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.33-0.94; p=0.028), and a positive association was found for having ?1 mutation in a DNA methylation-related gene: TET2, DNMT3A, IDH1 and/or IDH2 (OR: 4.76, 95%CI: 1.31-17.27; p=0.017). Mutations in TP53 (hazard ratio [HR]: 3.88; 95%CI: 1.94-7.75) and EZH2 (HR: 2.50; 95%CI: 1.23-5.09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n=815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes: ASXL1, CBL, EZH2, SF3B1, SRSF2, TET2, DNMT3A, IDH1/2 and TP53. TET2 mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR: 1.67, 95%CI: 1.14-2.44; p=0.01). In conclusion, mutations in the DNA methylation pathway, especially TET2 mutations, and low number of total mutations are associated with a better response to azacitidine.
| S-EPMC5739787 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
| S-EPMC3837510 | biostudies-other
Project description:Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal–truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multi-lineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2–mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT–induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS.
| S-EPMC3809801 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoeitic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia (AML). For decades, the mainstay of treatment for MDS was supportive care, including transfusion of blood products and growth factors. Further understanding of disease biology led to the discovery of a high prevalence of hypermethylation of tumor suppressor genes in high-risk MDS and secondary leukemias. Hence, the role of irreversible DNA methlytransferase inhibitors such as azacitidine was investigated with promising outcomes in the treatment of MDS. Azacitidine was initially approved in the USA by the Food and Drug Administration (FDA) in 2004 for the treatment of all subtypes of MDS and was granted expanded approval in 2009 to reflect new overall survival data demonstrated in the AZA-001 study of patients with higher-risk MDS. Azacitidine has demonstrated significant and clinically meaningful prolongation of survival in higher-risk patients with MDS and has changed the natural history of these disorders. The agent maintains a relatively safe toxicity profile, even in older patients. The role of azacitidine has been explored in the treatment of AML and chronic myelomonocytic leukemia and has also been studied in the peritransplant setting. Azacitidine has been combined with other novel agents such as lenalidomide, histone deacetylase inhibitors and growth factors in the hope of achieving improved outcomes. Currently, both intravenous and subcutaneous forms of azacitidine are approved for use in the USA with the oral form being granted fast track status by the FDA.
| S-EPMC3627328 | biostudies-literature
Project description:BackgroundEpigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic.ResultsUnsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress.ConclusionsOur findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
| S-EPMC7809812 | biostudies-literature
Project description:BackgroundImmunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients with lower-risk myelodysplastic syndrome (MDS). Age, human leukocyte antigen (HLA)-DR15 positivity, and duration of transfusion dependence are putative clinical variables predictive for response. We investigated the effect of somatic gene mutations on response to IST in lower-risk MDS.Patients and methodsForty of 66 patients who received antithymocyte globulin with or without cyclosporine A identified at the Moffitt Cancer Center were molecularly profiled using a 49-gene myeloid panel. All patients profiled received antithymocyte globulin, and cyclosporine A was provided to 60% of patients.ResultsThe overall frequency of HI was 42%. Presence of a large granular lymphocytic clone, hypocellular bone marrow, HLA-DR15 positivity, trisomy 8, and age had no influence on response to IST. Among 40 patients evaluated by next-generation sequencing, the presence of an SF3B1 mutation (MT) was significantly associated with IST nonresponse (1 of 9 SF3B1 MT, 11% vs. 21 of 31 wild type, 68%; P = .002). All patients with SF3B1 MT had ring sideroblasts > 15% (RS) by morphology; the corresponding HI rate was 20% among patients with RS versus 50% for those without RS (P = .09).ConclusionThese findings support the clinical implementation of genomics in MDS. The presence of an SF3B1 mutation adversely influences response to IST and should be incorporated into treatment decisions upon validation of these findings.
| S-EPMC7771378 | biostudies-literature
Project description:Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS). Pre-transplant debulking treatment have been employed for advanced MDS and we previously reported that marrow response (blast ≤ 5%) following the bridging therapy with hypomethylating agent was an independent favorable factor for survival; however, it is still not clear which patients will respond to hypomethylating agent and which genomic features can predict the response. In this study, we performed RNAseq for 23 MDS patients among which 14 (61%) and 9 (39%) patients showed marrow complete remission and primary resistance to azacitidine, respectively. Differential expression-based analyses of treatment-naive, baseline gene expression profiles revealed that molecular functions representing mitochondria and apoptosis were up-regulated in responders. In contrast, we identified genes involved in the Wnt pathway were relatively up-regulated in non-responders. In independent validation cohorts of MDS patients, the expression of gene sets specific to non-responders and responders distinguished the patients with favorable prognosis and those responded to azacitidine highlighting the prognostic and predictive implication. In addition, a systems biology approach identified genes involved in ubiquitination, such as UBC and PFDN2, which may be key players in the regulation of differential gene expression in treatment responders and non-responders. Taken together, identifying the gene expression signature may advance our understanding of the molecular mechanisms of azacitidine and may also serve to predict patient responses to drug treatment.
| S-EPMC7658235 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell-based disorders characterized by ineffective hematopoiesis, increased genomic instability and a tendency to progress toward acute myeloid leukemia (AML). MDS and AML cells present genetic and epigenetic abnormalities and, due to the heterogeneity of these molecular alterations, the current treatment options remain unsatisfactory. Hypomethylating agents (HMA), especially azacitidine, are the mainstay of treatment for high-risk MDS patients and HMA are used in treating elderly AML. The aim of this study was to investigate the potential role of the epigenetic reader bromodomain-containing protein-4 (BRD4) in MDS and AML patients. We identified the upregulation of the short variant BRD4 in MDS and AML patients, which was associated with a worse outcome of MDS. Furthermore, the inhibition of BRD4 in vitro with JQ1 or shRNA induced leukemia cell apoptosis, especially when combined to azacitidine, and triggered the activation of the DNA damage response pathway. JQ1 and AZD6738 (a specific ATR inhibitor) also synergized to induce apoptosis in leukemia cells. Our results indicate that the BRD4-dependent transcriptional program is a defective pathway in MDS and AML pathogenesis and its inhibition induces apoptosis of leukemia cells, which is enhanced in combination with HMA or an ATR inhibitor.
| S-EPMC6361844 | biostudies-literature
Project description:5-Azacitidine, a cytidine analogue used as a hypomethylating agent, is one of the main drugs for the treatment of myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) in the elderly. However, after administration, it exhibits several limitations, including restricted diffusion and cellular internalization due to its hydrophilicity, and a rapid enzymatic degradation by adenosine deaminase. The aim of this study was to improve the drug cell diffusion and protect it from metabolic degradation via the synthesis of amphiphilic prodrugs and their potential self-assembly. Azacitidine was conjugated to two different omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The carboxylic acid group of the omega-3 fatty acids was effectively conjugated to the amine group of the azacitidine base, yielding two amphiphilic prodrugs. Nanoprecipitation of the obtained prodrugs was performed and self-assemblies were successfully obtained for both prodrugs, with a mean diameter of 190 nm, a polydispersity index below 0.2 and a positive zeta potential. The formation of self-assemblies was confirmed using pyrene as a fluorescent dye, and the critical aggregation concentrations were determined: 400 µM for AzaEPA and 688 µM for AzaDHA. Additionally, the stability of the obtained self-assemblies was studied and after 5 days their final stable arrangement was reached. Additionally, cryo-TEM revealed that the self-assemblies attain a multilamellar vesicle supramolecular structure. Moreover, the obtained self-assemblies presented promising cytotoxicity on a leukemia human cell line, having a low IC50 value, comparable to that of free azacitidine.
| S-EPMC8706301 | biostudies-literature
Project description:Mesenchymal stromal cells (MSC) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival and differentiation of hematopoietic stem/progenitor cells (HSPC) in the stem cell niche. MSC are functionally and phenotypically altered in myelodysplastic syndromes (MDS), contributing to disease progression. MDS MSC do not harbor recurrent genetic alterations but have been shown to exhibit an altered methylome compared to MSC from healthy controls. We examined growth, differentiation and HSPC-supporting capacity of ex vivo expanded MSC from MDS patients in comparison to age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). We show that AZA exerts a direct effect on MSC by modulating their differentiation potential. Osteogenesis was significantly boosted in healthy MSC while adipogenesis was inhibited in both healthy and MDS MSC. In co-culture experiments, both AZA treated MDS MSC and healthy MSC exhibited enhanced support of non-clonal HSPC which was associated with increased cell cycle induction. Conversely, clonal MDS HSPC were inhibited by contact with AZA treated MSC. RNA-sequencing analyses of stromal cells revealed changes in pathways essential for HSPC support as well as in immune regulatory pathways. In sum, our data demonstrate that AZA treatment of stromal cells leads to upregulation of HSPC-supportive genes and cell cycle induction in co-cultured healthy HSPC, resulting in a proliferative advantage over clonal HSPC. Thus, restoration of functional hematopoiesis by AZA may be driven by activated stromal support factors in MSC providing cell cycle cues to healthy HSPC.
2018-12-19 | GSE112461 | GEO