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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

ABSTRACT: UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

PROVIDER: PRJNA955261 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24162117_1.fastq.gz	Fastqsanger.gz
	SRR24162117_2.fastq.gz	Fastqsanger.gz
	SRR24162118_1.fastq.gz	Fastqsanger.gz
	SRR24162118_2.fastq.gz	Fastqsanger.gz
	SRR24162119_1.fastq.gz	Fastqsanger.gz

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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

Project description:UBTF tandem duplications (TD) have recently emerged as a subtype-defining alteration in pediatric acute myeloid leukemia (pAML), which is characterized by HOXB gene dysregulation and a poor response to conventional chemotherapy. Here, we use protein-protein interaction studies to show that UBTF-TD maintains interactions with components of the RNA pol I complex, while also engaging with a network of unique protein interactors specific to UBTF-TD, like KMT2A. These data suggest that UBTF- TD both preserves canonical UBTF functions and demonstrates gain of function activities. Furthermore, we show that UBTF-TD and KMT2A co-localize to key genomic targets dysregulated in UBTF-TD myeloid malignancies, like HOXB gene clusters and MEIS1. Using a protein degradation system, we show that stemness, proliferation, and the HOXB molecular signature are dependent on sustained UBTF-TD localization to chromatin. Finally, we show UBTF-TD leukemias are sensitive to menin inhibition—providing a viable therapeutic strategy for children with this high-risk AML subtype.

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Project description:To investigate the effect of Menin inhibitor on UBTF-TD harboring AML. We characterized UBTF-TD interaction with KMT2A and Menin in different leukemia models including KMT2A-r, transduced and normal cbCD34+ cells as well as in primary AML cells with UBTF-TD mutation. We also analized gene expression pattern upon treatment with Menin inhibitor.

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Tandem duplications in UBTF create XPO1-dependent nuclear export signals necessary for leukemic progression [scRNA-seq]

Project description:UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML) characterized by poor clinical outcomes. While menin inhibitors have shown therapeutic promise, acquired resistance remains a significant challenge. Here, we use proteomic, genomic, and functional analyses to uncover mechanisms underlying UBTF-TD mediated leukemogenesis. We show that TDs create nuclear export signal (NES) motifs, which mediate interactions with Exportin-1 (XPO1) and chromatin-associated partners. These interactions drive aberrant chromatin binding and transcriptional activation of genes commonly dysregulated in UBTF-TD tumors, including the HOXA/HOXB clusters. We demonstrate that these NES motifs are critical for mislocalization of UBTF-TD proteins, cellular transformation, and transcriptional dysregulation. Importantly, we identify the XPO1 inhibitor eltanexor as a potential therapeutic strategy. Eltanexor treatment disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation in preclinical models. These findings provide mechanistic insights into UBTF-TD-driven leukemogenesis and highlight XPO1 inhibition as a promising therapy for UBTF-TD AMLs.

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Tandem duplications in UBTF create XPO1-dependent nuclear export signals necessary for leukemic progression [CUT&Run]

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Tandem duplications in UBTF create XPO1-dependent nuclear export signals necessary for leukemic progression [RNA-seq]

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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition

Project description:This SuperSeries is composed of the SubSeries listed below.

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