RNA sequencing of human, IDH2-mutated, acute myeloid leukemia samples from patients before or during treatment with Enasidenib

Mutations in isocitrate dehydrogenase 2 (IDH2) occur in many cancers including Acute Myeloid Leukemia (AML). Recently, we showed that single agent Enasidenib, a first-in-class, selective mutant IDH2 inhibitor, produces a 40% response in relapsed/refractory AML patients by promoting differentiation of leukaemic cells. In this current study, we describe two patients who responded to Enasidenib treatment but subsequently relapsed with an IDH2-mutant subclone which had acquired mutations in DHX15 and DDX1 genes. These genes have putative functions in regulating splicing. We have studied the alternative splicing events using RNASeq in the sample pre-relapse (before acquisition of DHX15 and DDX1 mutations) and at relapse (after acquisition of DHX15 and DDX1 mutations).