Identification of the dismal subtype of B-ALL with dysregulation of CDX2 and UBTF
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ABSTRACT:
PROVIDER: PRJNA787963 | ENA |
REPOSITORIES: ENA
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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.
| EGAS00001005863 | EGA
Project description:A) Chromatins were prepared from Cdx2-inducible ES cells cultured for 48 - 60 hours in the Dox+ and Dox- conditions. Chromatin immunoprecipitation (ChIP) was carried out by using anti-FLAG M2 affinity gel. ChIP product was tested by Western blotting using anti-FLAG antibody. Nuclear extract from ES cells cultured for 48 - 60 hours in Dox+ and Dox- condition was used for the Western blot. B) CDX2 ChIP-Seq peaks in the Hoxa7 gene region. UCSC Mouse Mm9 browser view of Hoxa7 gene locus after mapping CDX2 ChIP-Seq tags locations in the wiggle format. CDX2 ChIP-Seq peaks are shown in red color. C) Cdx2 ChIP-Seq result was verified by qPCR. Target genes were indicated in (G). Primers flanking a promoter region of Hbb-b1 and Pou5f1 as well as a gene desert region in chromosome 3 were used as negative controls. Primers flanking of Actb gene promoter were used for normalization. The relative enrichment of CDX2 binding was indicated as fold change. (D) CDX2-binding motifs identified with CisFinder using 200 bp sequences centered at ChIP sites. (F) Potential CDX2-direct target genes based on ChIP-Seq and the alteration of expression by Cdx2-overexpression. (G) Identification of CDX2 target genes by combining information on binding sites with gene expression response to Cdx2 over-expression Chromatin IP against CDX2-Flag fusion protein. MC1 ES cells were genetically modified for ROSA26 locus to have Tet-Off expression cassette for C-terminal FLAG tagged Cdx2. The peaks are obtained from the Eland Multi Alignment file. The number of tags in peaks was compared with the number of tags in the control sample for the same region corrected by the total coverage of tags. See supplemental file of the paper for details.
2009-10-01 | E-GEOD-14586 | biostudies-arrayexpress
Project description:A) Chromatins were prepared from Cdx2-inducible ES cells cultured for 48 - 60 hours in the Dox+ and Dox- conditions. Chromatin immunoprecipitation (ChIP) was carried out by using anti-FLAG M2 affinity gel. ChIP product was tested by Western blotting using anti-FLAG antibody. Nuclear extract from ES cells cultured for 48 - 60 hours in Dox+ and Dox- condition was used for the Western blot. B) CDX2 ChIP-Seq peaks in the Hoxa7 gene region. UCSC Mouse Mm9 browser view of Hoxa7 gene locus after mapping CDX2 ChIP-Seq tags locations in the wiggle format. CDX2 ChIP-Seq peaks are shown in red color. C) Cdx2 ChIP-Seq result was verified by qPCR. Target genes were indicated in (G). Primers flanking a promoter region of Hbb-b1 and Pou5f1 as well as a gene desert region in chromosome 3 were used as negative controls. Primers flanking of Actb gene promoter were used for normalization. The relative enrichment of CDX2 binding was indicated as fold change. (D) CDX2-binding motifs identified with CisFinder using 200 bp sequences centered at ChIP sites. (F) Potential CDX2-direct target genes based on ChIP-Seq and the alteration of expression by Cdx2-overexpression. (G) Identification of CDX2 target genes by combining information on binding sites with gene expression response to Cdx2 over-expression
2009-10-01 | GSE14586 | GEO
Project description:Somatic DNA alteration underlies tumor development and progression, and gives rise to tumors with diverse genetic contexts. Here, we identify in a collection of 29 colorectal cancer cell lines and 226 primary colorectal tumors recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor CDX2, a master regulator of anterior-posterior patterning, midgut development, and intestinal epithelial cell differentiation and maintenance. In contrast to its described role as a colorectal tumor suppressor, we show that in the context of genomic amplification, CDX2 is required for proliferation and anchorage-independent growth of colorectal cancer cells. By genome-wide expression and location analysis, we reveal that CDX2 directly promotes expression of Wnt pathway genes. Further results suggest that CDX2 induces expression of intestinal differentiation markers and modulates β-catenin transcriptional activity. These data characterize CDX2 as a novel lineage-survival oncogene deregulated in colorectal cancer. ChIP-seq analysis of CDX2 binding sites in COLO320 cells
2012-11-02 | E-GEOD-30026 | biostudies-arrayexpress
Project description:Somatic DNA alteration underlies tumor development and progression, and gives rise to tumors with diverse genetic contexts. Here, we identify in a collection of 29 colorectal cancer cell lines and 226 primary colorectal tumors recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor CDX2, a master regulator of anterior-posterior patterning, midgut development, and intestinal epithelial cell differentiation and maintenance. In contrast to its described role as a colorectal tumor suppressor, we show that in the context of genomic amplification, CDX2 is required for proliferation and anchorage-independent growth of colorectal cancer cells. By genome-wide expression and location analysis, we reveal that CDX2 directly promotes expression of Wnt pathway genes. Further results suggest that CDX2 induces expression of intestinal differentiation markers and modulates β-catenin transcriptional activity. These data characterize CDX2 as a novel lineage-survival oncogene deregulated in colorectal cancer.
2012-11-02 | GSE30026 | GEO
Project description:Regulatory proteins can bind to different sets of genomic targets in various cell types or conditions. To reliably characterize such condition-specific regulatory binding we introduce MultiGPS, an integrated machine learning approach for the analysis of multiple related ChIP-seq experiments. MultiGPS is based on a generalized Expectation Maximization framework that shares information across multiple experiments for binding event discovery. We demonstrate that our framework enables the simultaneous modeling of sparse condition-specific binding changes, sequence dependence, and replicate-specific noise sources. MultiGPS encourages consistency in reported binding event locations across multiple-condition ChIP-seq datasets and provides accurate estimation of ChIP enrichment levels at each event. MultiGPSM-bM-^@M-^Ys multi-experiment modeling approach thus provides a reliable platform for detecting differential binding enrichment across experimental conditions. We demonstrate the advantages of MultiGPS with an analysis of Cdx2 binding in three distinct developmental contexts. By accurately characterizing condition-specific Cdx2 binding, MultiGPS enables novel insight into the mechanistic basis of Cdx2 site selectivity. Specifically, the condition-specific Cdx2 sites characterized by MultiGPS are highly associated with pre-existing genomic context, suggesting that such sites are pre-determined by cell-specific regulatory architecture. However, MultiGPS-defined condition-independent sites are not predicted by pre-existing regulatory signals, suggesting that Cdx2 can bind to a subset of locations regardless of genomic environment. In this study, we characterize the binding of Cdx2 in embryonic stem cells, endodermal cells, and progenitor motor neurons using V5- or FLAG-tagged doxycycline inducible Cdx2 ESC lines (iCdx2). Endoderm and progenitor motor neurons are generated from the ES cells using directed differentiation approaches. The cells are then exposed to Dox to express the tagged Cdx2 construct. The genome-wide binding of the induced full-length Cdx2 transcription factor is profiled using ChIP-seq with an anti-V5 or anti-FLAG antibody. We also examine the binding behavior of a truncated version of the Cdx2 protein, where a protein interaction domain contained in the first 59 amino acids has been deleted. An appropriate pseudo-IP control experiment for these ChIP-seq experiments has been previously submitted under accession number GSM766062.
2014-03-27 | E-GEOD-39435 | biostudies-arrayexpress
Project description:Most colorectal cancers (CRCs) are moderately-differentiated or well-differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a novel post-transcriptional regulation mechanism via a previously unappreciated LIN28B-CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration and tumorigenesis. Our RNA-binding protein immunoprecipitation (RIP) assay revealed LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression results in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition. Chromatin immunoprecipitation (ChIP) sequence for CDX2 identified Alpha-Methylacyl-CoA racemase (AMACR) as a novel transcriptional target of CDX2 in the context of LIN28B overexpression. Overall, we demonstrate that LIN28B promotes CRC differentiation through CDX2-AMACR axis.
2021-01-28 | GSE165674 | GEO
Project description:Placental Cdx2 cells can be isolated and utilized for cardiac regeneration in a mouse model of myocardial infarction with evidence of multipotentiality both in vitro and in vivo
2019-05-09 | PXD011783 | Pride
Project description:Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of AML expressing CDX2, and observed that PPARγ agonists derepress KLF4 and are preferentially toxic to CDX2-positive leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells; provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer; and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a new therapeutic modality in a large proportion of AML patients.
2012-12-21 | GSE40939 | GEO