Identification of the dismal subtype of B-ALL with dysregulation of CDX2 and UBTF
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ABSTRACT:
PROVIDER: PRJNA787963 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17200118_1.fastq.gz | Fastqsanger.gz | |||
| SRR17200118_2.fastq.gz | Fastqsanger.gz | |||
| SRR17200119_1.fastq.gz | Fastqsanger.gz | |||
| SRR17200119_2.fastq.gz | Fastqsanger.gz |
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Project description:A new subtype of B-ALL was identified through integrative genomic analysis and H3K27ac HiChIP was used to investigate impact of structural variants on the CDX2-FLT3-PAN3 genomic region
2021-12-17 | GSE190690 | GEO
Project description:PURPOSE: Advance in the knowledge of genomic basis of B-cell acute lymphoblastic leukemia (B-ALL) has changed the treatment approaches and diagnostic assays and improved their outcome. Despite the recent development of next generation sequencing approaches, there are still some cases that their drivers are unknown. We aimed to define and describe the characteristics of an additional B-ALL subtype by integrating genomic, transcriptomic, and epigenomic approach.
METHODS: More than 2,000 B-ALL cases of RNA-seq data from from Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) (n=764), the Children's Oncology Group (COG), Munich Leukemia Laboratory (MLL) (n=280), and other several collaborators were analyzed to identify the new subtype. Whole genome sequence was performed to detect mutations, stractural variants, and copy number alterations. The tridimentional analysis of chromatin was performed with HiChIP.
RESULTS: We identified the new high-risk B-ALL subtype “CDX2/UBTF†that exhibited unique gene expression profiles, which is enriched in female (77.3%), adolescents and young adults (52.6%), and relapse cohort (3.3%). CD10 negativity and IgM positivity are hallmarks of this subtype with NTRK3 expression that can be an effective marker at diagnostic approach and a potential targeted therapy with TRK and mulkinase inbitors, larotrectinib and entrectinib. Genetically, two different alterations define CDX2/UBTF. One is UBTF-ATXN7L3 fusions caused by deletion of 17q21.31, and the other is extopic CDX2 expression through the enhancer hijacking mechanism induced by deletion of 13q12.2. Other genomic features include gain of 1q and PAX5 rearrangement (PAX5-ZCCHC7), might induce upregulation of histone cluster genes and PAX5.
CONCLUSION: We described the novel B-ALL subtype “CDX2/UBTF†that has unique clinical and genomic characteristics.
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Project description:UBTF tandem duplications (TD) have recently emerged as a subtype-defining alteration in pediatric AML (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 leukemias, 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: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: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: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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