Data from <i>PHF6</i>-altered T-ALL Harbor Epigenetic Repressive Switch at Bivalent Promoters and Respond to 5-Azacitidine and Venetoclax

Abstract

<div>AbstractPurpose:<p>To assess the impact of PHF6 alterations on clinical outcome and therapeutical actionability in T-cell acute lymphoblastic leukemia (T-ALL).</p>Experimental Design:<p>We described PHF6 alterations in an adult cohort of T-ALL from the French trial Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 and retrospectively analyzed clinical outcomes between PHF6-altered (PHF6<sup>ALT</sup>) and wild-type patients. We also used EPIC and chromatin immunoprecipitation sequencing data of patient samples to analyze the epigenetic landscape of PHF6<sup>ALT</sup> T-ALLs. We consecutively evaluated 5-azacitidine efficacy, alone or combined with venetoclax, in PHF6<sup>ALT</sup> T-ALL.</p>Results:<p>We show that PHF6 alterations account for 47% of cases in our cohort and demonstrate that PHF6<sup>ALT</sup> T-ALL presented significantly better clinical outcomes. Integrative analysis of DNA methylation and histone marks shows that PHF6<sup>ALT</sup> are characterized by DNA hypermethylation and H3K27me3 loss at promoters physiologically bivalent in thymocytes. Using patient-derived xenografts, we show that PHF6<sup>ALT</sup> T-ALL respond to the 5-azacytidine alone. Finally, synergism with the BCL2-inhibitor venetoclax was demonstrated in refractory/relapsing (R/R) PHF6<sup>ALT</sup> T-ALL using fresh samples. Importantly, we report three cases of R/R PHF6<sup>ALT</sup> patients who were successfully treated with this combination.</p>Conclusions:<p>Overall, our study supports the use of PHF6 alterations as a biomarker of sensitivity to 5-azacytidine and venetoclax combination in R/R T-ALL.</p></div>