Identification of ID4 as a Cooperating Second Hit for T Cell Lymphoma Development in PU.1 UREΔ/Δ Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2613-2613
Author(s):  
Bronwyn M. Owens ◽  
Li Yu ◽  
Ulrich Steidl ◽  
Jeffrey L. Kutok ◽  
Linda K. Clayton ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Regulatory Element ◽  
Tumor Development ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Promoter Regions ◽  
Hematopoietic Stem

Abstract The transcription factor PU.1 is a key regulator of hematopoiesis and is essential for normal hematopoietic stem cell (HSC) function and myeloid and lymphoid differentiation. Knockout mice are embryonic or neonatal lethal and exhibit an early differentiation block at the transition from HSC to CMP and CLP. Mice with a deletion of a critical upstream regulatory element (URE) at −14kb has been deleted exhibited decreased PU.1 expression in HSC, progenitors and B cells to 20% of normal levels. In contrast, an increase of PU.1 expression was detected in early thymic progenitors. UREΔ/Δ animals exhibited a block in normal thymocyte differentiation and frequently progressed to fatal T cell lymphomas between 3 and 8 months of age. Tumors were clonal and transplantable into NOD-SCID recipients. Since aberrant PU.1 expression constituted the initiating mutation, we sought to identify cooperating mutations contributing to tumor development by surveying the genome for hypermethylated promoter regions using restriction landmark global scanning. Methylation patterns revealed a characteristic epigenetic footprint leading to selective tumor suppressor gene silencing in transformation of lymphoid but not myeloid UREΔ/Δ progenitors, since DNA methylation was significantly lower in the AML samples compared with lymphomas. One of the corresponding methylated genes that was silenced in all lymphomas analyzed but none of the AMLs was identified as Idb4 (encoding ID4, inhibitor of DNA binding 4). This observation is consistent with data describing ID4 as a strong tumor suppressor gene which is frequently silenced in neoplasms. The expression of Idb4 in 6 additional lymphomas was assessed by quantitative RT-PCR and showed a strong correlation between promoter hypermethylation and Idb4 downregulation. To test whether Idb4 silencing through promoter hypermethylation can be pharmacologically reversed, a UREΔ/Δ lymphoma cell line was established and treated with 5-aza-2′deoxycytidine. We found that Idb4 expression was restored to normal levels following increasing concentrations of this demethylating agent. Finally, we analyzed the functional relevance of the Idb4 downregulation by restoring Idb4 expression in the UREΔ/Δ tumor line. UREΔ/Δ lymphoma cells reexpressing Idb4 had a marked reduction in both the in vitro growth rate and the ability to cause tumors after transplantation into NOD/SCID recipient mice, indicating that Idb4 is a potent suppressor of UREΔ/Δ thymic tumorigenicity. Taken together, we provide evidence that epigenetic DNA modifications contribute significantly and selectively to lymphoid transformation in UREΔ/Δ mice, and suggest a role for Idb4 repression as a second event in PU.1-initiated transformation of lymphoid precursors.

scholarly journals Hypermethylation of heparanase 2 promotes colorectal cancer proliferation and is associated with poor prognosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hui Zhang ◽  
Chenxin Xu ◽  
Chen Shi ◽  
Junying Zhang ◽  
Ting Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Promoter Methylation ◽  
Genomic Analysis ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
The Cancer Genome Atlas

Abstract Background The epigenetic abnormality of tumor-associated genes contributes to the pathogenesis of colorectal carcinoma (CRC). However, methylation in colorectal cancer is still poorly characterized. Method By integration of DNA methylation data from the GEO database and gene expression data from The Cancer Genome Atlas database, the aberrantly methylated genes involved in CRC tumorigenesis were identified. Subsequent in vitro experiments further validated their role in CRC. Results We performed integrative genomic analysis and identified HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. K-M survival analysis showed that hypermethylation–low expression of heparanase 2 (HPSE2) was related to poor patient prognosis. Overexpression of HPSE2 reduced cell proliferation in vivo and in vitro. HPSE2 could regulate the p53 signaling pathway to block the cell cycle in G1 phase. Conclusion HPSE2, a novel tumor suppressor gene that is frequently inactivated through promoter methylation in CRC. HPSE2 performs a tumor suppressive function by activating the p53/ p21 signaling cascade. The promoter hypermethylation of HPSE2 is a potential therapeutic target in patients with CRC, especially those with late-stage CRC.

scholarly journals Correction: Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified

2019 ◽  
Vol 33 (2) ◽  
pp. 319-319
Author(s):  
Maria Antonella Laginestra ◽  
Luciano Cascione ◽  
Giovanna Motta ◽  
Fabio Fuligni ◽  
Claudio Agostinelli ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Tumor Suppressor Gene ◽  
Whole Exome Sequencing ◽  
Cell Lymphoma ◽  
Suppressor Gene ◽  
Peripheral T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
Whole Exome

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Whole exome sequencing reveals mutations in FAT1 tumor suppressor gene clinically impacting on peripheral T-cell lymphoma not otherwise specified

2019 ◽  
Vol 33 (2) ◽  
pp. 179-187 ◽  
Author(s):  
Maria Antonella Laginestra ◽  
Luciano Cascione ◽  
Giovanna Motta ◽  
Fabio Fuligni ◽  
Claudio Agostinelli ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Exome Sequencing ◽  
Tumor Suppressor Gene ◽  
Whole Exome Sequencing ◽  
Cell Lymphoma ◽  
Suppressor Gene ◽  
Peripheral T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
Whole Exome

scholarly journals Disruption of the Multiple Tumor Suppressor Gene MTS1/p16INK4a/CDKN2 by Illegitimate V(D)J Recombinase Activity in T-Cell Acute Lymphoblastic Leukemias

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3720-3726 ◽  
Author(s):  
Jean-Michel Cayuela ◽  
Betty Gardie ◽  
François Sigaux
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Genetic Event ◽  
Ca Repeat ◽  
Multiple Tumor ◽  
Human T Cell ◽  
Exon 1 ◽  
Cell Cycle Inhibitors

Abstract We have recently shown that the multiple tumor suppressor gene 1 (MTS1 ) encoding the p16INK4a and p19ARF cell-cycle inhibitors is inactivated by deletion or disruption in most human T-cell acute lymphoblastic leukemias (T-ALLs), representing the most frequent genetic event thus far described in this disease. To analyze the mechanism of these chromosomal events, we used cloning, sequencing, and/or polymerase chain reaction mapping to study 15 rearrangements occurring in the MTS1 locus. We found that these breakpoints occur in two clusters (MTS1bcrα and MTS1bcrβ ). The three rearrangements occurring in MTS1bcrα correspond to a recurrent recombination juxtaposing 5′ MTS2 exon 1 and 5′ MTS1 exon 1α sequences. Breakpoints for 10 of 12 rearrangements within MTS1bcrβ are located at a polymorphic (CA) repeat, suggesting that this sequence might play a role in the clustering. For both MTS1bcrα and MTS1bcrβ, sequence analyses and PCR mapping experiments show that the tightly clustered breakpoints are located in the vicinity of heptamers whose sequence is similar to those involved in the V(D)J recombination. Moreover, short deletions, GC-rich random nucleotide additions, and clone-specific junctional sequences are present in all cases, further suggesting that the rearrangements are due to illegitimate V(D)J recombinase activity. These data are the first demonstration that a tumor suppressor gene can be inactivated by the V(D)J recombinational mechanism. Moreover, they reinforce the view that this process, normally required for T-cell differentiation, plays a crucial role in the pathogenesis of T-ALL.

Detailed Deletion Mapping of the Long Arm of Chromosome 6 in Adult T-Cell Leukemia

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 613-616 ◽  
Author(s):  
Yoshihiro Hatta ◽  
Yasuaki Yamada ◽  
Masao Tomonaga ◽  
Isao Miyoshi ◽  
Jonathan W. Said ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Deletion Mapping ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Putative Tumor Suppressor Gene ◽  
Adult T Cell Leukemia ◽  
Putative Tumor Suppressor

Abstract Previously, we have found that the loss of heterozygosity (LOH) was frequently observed on chromosome 6q in acute/lymphoma-type adult T-cell leukemia (ATL), suggesting a putative tumor-suppressor gene for ATL may be present on chromosome 6q. To further define a region containing this gene, we performed fine-scale deletional mapping of chromosome 6q in 22 acute/lymphomatous ATL samples using 24 highly informative microsatellite markers. LOH was found in 9 samples (40.9%) at 1 or more of the loci examined. Of the 9 samples, 8 shared the same smallest commonly deleted region flanked by D6S1652 and D6S1644 (6q15-21). The genetic distance between these two loci is approximately 4 cM. These results suggest that a putative tumor-suppressor gene on chromosome 6q15-21 probably plays a very important role in the evolution of acute/lymphomatous ATL. Our map provides key information toward cloning the gene.

scholarly journals The Cell Death Inhibitor ARC Is Induced in a Tissue-Specific Manner by Deletion of the Tumor Suppressor Gene Men1, but Not Required for Tumor Development and Growth

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0145792 ◽  
Author(s):  
Wendy M. McKimpson ◽  
Ziqiang Yuan ◽  
Min Zheng ◽  
Judy S. Crabtree ◽  
Steven K. Libutti ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Tissue Specific ◽  
Specific Manner
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