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PHF6-altered T-ALL harbored epigenetic repressive switch at bivalent promoters and respond to 5-azacitidine and venetoclax
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Edité par CCSD ; American Association for Cancer Research -
International audience. Purpose: To assess the impact of PHF6 alterations on clinical outcome andtherapeutical actionability in T cells acute lymphoblastic leukemia (T-ALL).Experimental Design: We described PHF6 alterations in an adult cohort of T-ALL fromthe French trial GRAALL 2003/2005 and retrospectively analyzed clinical outcomesbetween PHF6-altered (PHF6ALT) and wild-type patients. We also used EPIC andChIP-seq data of patient samples to analyze the epigenetic landscape of PHF6ALT T-ALLs. We consecutively evaluated 5-azacitidine efficacy, alone or combine withvenetoclax, in PHF6ALT T-ALL.Results: We show that PHF6 alterations account for 47% of cases in our cohort anddemonstrate that PHF6ALT T-ALL presented significantly better clinical outcomes.Integrative analysis of DNA methylation and histone marks shows that PHF6ALT arecharacterized by DNA hypermethylation and H3K27me3 loss at promotersphysiologically bivalent in thymocytes. Using patient-derived xenografts (PDX), weshow that PHF6ALT T-ALL respond to the 5-azacytidine alone. Finally, synergism withthe BCL2-inhibitor venetoclax was demonstrated in refractory/relapsing PHF6ALT T-ALL using fresh samples. Importantly, we report three cases of refractory/relapsed(R/R) PHF6ALT patients who were successfully treated with this combination.Conclusions: Overall, our study supports the use of PHF6 alterations as a biomarkerof sensitivity to 5-azacytidine and venetoclax combination in R/R T-ALL.
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