New Treatment Opportunity for Acute Myeloid Leukemias Harbouring a UBTF Tandem Duplication

Abstract

Tandem duplications in the upstream binding transcription factor (UBTF-TD) have been recently identified as a recurrent mutation in pediatric acute myeloid leukemia (AML). They are seen in 4% of de novo patients and 9% of relapse cases. Transcriptionally similar AML subtypes, such as MLL-rearranged, NUP98- rearranged, and NPMI-mutant AMLs, were found to respond to small molecular inhibitors to the menin-MLL1 interaction which is critical for leukemogenesis. We hypothesized that due to similarities in the oncogenic programs of these AML subtypes with AMLs harboring the UBTF-TD alteration, implementation of Menin inhibitors could lead to a reduction in the leukemic characteristic of UBTF-TD AMLs. This hypothesis was tested by treating primary UBTF-TD AML cells with the Menin inhibitor SNDX-5613 (Revumenib) and looking at its effect on global gene expression via RT-qPCR and RNA sequencing. Since UBTF-TD AMLs are often accompanied by FLT3-ITDs, we also looked at the effect of SNDX-5613 and its combination with an FLT3 inhibitor on this protein through phopho-STAT5 signaling pathway analysis. We found that Menin inhibition substantially changed global gene expression of UBTF-TD AMLs, including downregulation of important downstream target genes that depend upon the Menin-MLL interaction and upregulation of differentiation markers. Phospho-STAT5 signaling analyzed by flow cytometry revealed that individual treatment was as effective (Gilteritinib) or more effective (SNDX-5613) than combination treatment.