Project description:5-azacytidine (AZA) is widely used for treatment of myelodysplastic syndromes (MDS). However, identifying predictive factors for response to AZA remains challenging. The aim in present study was to identify the genes which are susceptible to AZA in MDS and investigate the possibility of the gene for predictor for response to AZA therapy. To identify AZA-susceptible genes, we compared the gene expression changes by AZA in MDS-L cells (AZA-sensitive) with those in MDS-L/CDA cells (AZA-resistant) in culture. Of 438 AZA-susceptible genes, we searched the genes which are hypermethylated in MDS patients as compared to healthy controls by analyzing public dataset GSE152710, and found ALOX12 gene. Analysis of public dataset GSE145733 and GSE58831 revealed that ALOX12 expression was suppressed in MDS classes with excess blasts but not in other classes, and were negatively and positively correlated with bone marrow blast counts and survival, respectively, in MDS patients. Analysis of public dataset GSE152710 revealed that the methylation level of ALOX12 gene was decreased in MDS patients with complete remission but not in those with partial response and progression disease after AZA therapy. Our retrospective clinical study in which nine AZA-treated patients were enrolled suggested that ALOX12 expression was increased in patients with favorable response, while decreased in patient with poor response after AZA therapy. In conclusion, ALOX12 gene could be tumor suppressive and promising marker for predicting the response to AZA therapy in MDS.

2023-05-31 | GSE233764 | GEO

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses

Project description:Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective GLS inhibitor, when combined with azacytidine (AZA), in vitro and in vivo, followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with telaglenastat/AZA led to an ORR of 70% with CR/mCRs in 53% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells; was associated with clinical responses to telaglenastat/AZA and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.

2024-02-12 | GSE225352 | GEO

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