CDK4/6 Inhibitor, Palbociclib, overcomes Venetoclax resistance mechanisms and outperforms single agents in Acute Myeloid Leukemia [RNA-Seq]

Venetoclax (ven) combined with the hypomethylating agent azacytidine (aza) is a widely used therapy for Acute Myeloid Leukemia (AML), however, most patients develop resistance. Using RNASeq, we identified loss of Ikaros (IKZF1) as a potential resistance mechanism to ven+palbo. Examination of cells with IKZF1-loss revealed upregulation of the receptor, AXL, with concordant AXL inhibitor sensitivity in AML tumors harboring IKZF1 mutations. This work suggests that the combination of ven+palbo is a potential novel therapy for AML for potential subpopulations that may benefit the most from this treatment, as well as targeting translation as a means to overcome ven resistance. Overall design: Using RNA-Seq, we compared three OCI-AML2 cell lines with a IKZF1 knock-out to three others with a non-targeting control to identify differentially expressed genes associated with loss of IKZF1.