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A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [RNA-seq]

ABSTRACT: Cells carrying MLL-rearrangements are sensitive to treatment with VTP-50469 with IC50 in 20-60 nM. We treated MOLM13 or RS4;11 cells with DMSO (0.33%) or VTP-50469 (100-330nM), followed by digital gene expression analyses of 3'end RNA-seq data. We found that very few genes significantly change expression >2-fold after 2 days of treatment, while after 7-day treatment more genes significantly changed expression >2-fold. The genes that lost expression after VTP-50469 treatment were enriched in MLL-fusion target genes and DOT1L-sensitive genes. Moreover, treatment with both EPZ-5676 and VTP-50469 suppress similar subsets of genes, however VTP-50469 suppress genes faster as compared to EPZ-5676. Treatment of PDX with VTP-50469 suppressed similar gene sets, namely MLL-fusion targets and DOT1L-sensitive genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127506 | GEO | 2019/11/06

REPOSITORIES: GEO

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Project description:Purpose: The chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene have been extensively characterized as a potent oncogenic driver on the molecular and mechanistic level in acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. For its oncogenic function the MLL fusion protein is hijacking the the multi enzyme super elongation complex (SEC) leading to elevated expression of MLL target genes (e.g. HOXA9 and MEIS). High expression of MLL target genes is overwriting the normal hematopoietic differentiation gene expression program, resulting in undifferentiated blasts cells having a more “stem-cell like” cancer-promoting phenotype. Although extensive resources have been devoted to a better understanding of therapeutic targets for the MLL fusion to overcome the de-differentiation, the inter-dependencies of those targets for the pathophysiology of MLL is still barely understood. Here we report a comparative mode of action analysis of different inhibitors potentially interfering with MLL fusion induced differentiation blockade. We used RNA-seq for transcriptomic profiling in 14 AML and ALL cell lines treated with DMSO control or one of the 5 studied inhibitors (EPZ-5676, Brequinar, BAY-155, BAY-1251152 and OTX015). Methods: We used RNA-seq for transcriptomic profiling in 14 AML and ALL cell lines treated with DMSO control or one of the 5 studied inhibitors (EPZ-5676, Brequinar, BAY-155, BAY-1251152 and OTX015). Results: We discovered significant differences between compounds in their ability to induce differentiation and interfere with MLL target genes expression. We observed that Menin and DOT1L inhibition act very specifically on MLL fused leukemia cell lines, whereas inhibition of BET, DHODH and P-TEFb have strong effects beyond the MLL fusion . Conclusions: These results show a substantial diversity in the molecular activities of those inhibitors and provide valuable insights into the further developmental potential as single agents or in combinations in MLL fused leukemias.

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A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [RNA-seq]

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