scholarly journals Genetic analysis of Ikaros target genes and tumor suppressor function in BCR-ABL1+ pre–B ALL

2017 ◽  
Vol 214 (3) ◽  
pp. 793-814 ◽  
Author(s):  
Hilde Schjerven ◽  
Etapong F. Ayongaba ◽  
Ali Aghajanirefah ◽  
Jami McLaughlin ◽  
Donghui Cheng ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Target Genes ◽  
Lymphoblastic Leukemia ◽  
Suppressor Gene ◽  
Tumor Suppressor Function ◽  
Gene Encoding ◽  
Specific Expression ◽  
Suppressor Function ◽  
Genome Wide ◽  
Conserved Gene

Inactivation of the tumor suppressor gene encoding the transcriptional regulator Ikaros (IKZF1) is a hallmark of BCR-ABL1+ precursor B cell acute lymphoblastic leukemia (pre–B ALL). However, the mechanisms by which Ikaros functions as a tumor suppressor in pre–B ALL remain poorly understood. Here, we analyzed a mouse model of BCR-ABL1+ pre–B ALL together with a new model of inducible expression of wild-type Ikaros in IKZF1 mutant human BCR-ABL1+ pre–B ALL. We performed integrated genome-wide chromatin and expression analyses and identified Ikaros target genes in mouse and human BCR-ABL1+ pre–B ALL, revealing novel conserved gene pathways associated with Ikaros tumor suppressor function. Notably, genetic depletion of different Ikaros targets, including CTNND1 and the early hematopoietic cell surface marker CD34, resulted in reduced leukemic growth. Our results suggest that Ikaros mediates tumor suppressor function by enforcing proper developmental stage–specific expression of multiple genes through chromatin compaction at its target genes.

scholarly journals Loss of heterozygosity in the chromosomal region 12p12-13 is very common in childhood acute lymphoblastic leukemia and permits the precise localization of a tumor-suppressor gene distinct from p27KIP1

Blood ◽  
1995 ◽  
Vol 86 (10) ◽  
pp. 3869-3875 ◽  
Author(s):  
H Cave ◽  
B Gerard ◽  
E Martin ◽  
C Guidal ◽  
I Devaux ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Chromosomal Region ◽  
Lymphoblastic Leukemia ◽  
Chromosome Analysis ◽  
Hematologic Malignancies ◽  
Suppressor Gene ◽  
Gene Encoding ◽  
Putative Tumor Suppressor Gene

Abnormalities of the short arm of chromosome 12 are relatively common in hematologic malignancies and deletions of the region. 12p12–13 are found in approximately 5% of the patients with acute lymphoblastic leukemia (ALL). As a potent inhibitor of cyclin-dependent kinases, p27KIP1 prevents the progression of the cell cycle and the gene encoding p27KIP1 represents a potential tumor-suppressor gene. Its recent assignment to the chromosomal region (12p12.3) prompted us to study the p27KIP1 gene in a series of 61 children with ALL. Microsatellite polymorphic markers flanking the p27KIP1 gene were analyzed to detect losses of heterozygosity (LOH). Eleven patients displayed LOH for at least one of the markers. The deleted are encompassed the p27KIP1 gene locus in 10 cases, but inactivation of the remaining allele by deletion, translocation, or mutation was never observed. In addition, in 1 patient, the p27KIP1 gene was situated outside of the region of LOH. Thus, p27KIP1 does not seem to be the target gene of 12p12–13 alterations. However, this study indicates that 12p12–13 alterations at the molecular level, which are present in about 27% of the children with B-lineage ALL, are much more common than had previously been reported by usual chromosome analysis. Moreover, LOH mapping allowed us to better define the location of a putative tumor- suppressor gene implicated in these malignancies and should therefore help in identifying this gene.

scholarly journals Nuclear Heparanase Regulates Chromatin Remodeling, Gene Expression and PTEN Tumor Suppressor Function

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2038
Author(s):  
Rada Amin ◽  
Kaushlendra Tripathi ◽  
Ralph D. Sanderson
Keyword(s):  
Tumor Suppressor ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Myeloma Cell ◽  
Chromatin Accessibility ◽  
Tumor Suppressor Function ◽  
Suppressor Activity ◽  
Downstream Target ◽  
Suppressor Function ◽  
Chromatin Opening

Heparanase (HPSE) is an endoglycosidase that cleaves heparan sulfate and has been shown in various cancers to promote metastasis, angiogenesis, osteolysis, and chemoresistance. Although heparanase is thought to act predominantly extracellularly or within the cytoplasm, it is also present in the nucleus, where it may function in regulating gene transcription. Using myeloma cell lines, we report here that heparanase enhances chromatin accessibility and confirm a previous report that it also upregulates the acetylation of histones. Employing the Multiple Myeloma Research Foundation CoMMpass database, we demonstrate that patients expressing high levels of heparanase display elevated expression of proteins involved in chromatin remodeling and several oncogenic factors compared to patients expressing low levels of heparanase. These signatures were consistent with the known function of heparanase in driving tumor progression. Chromatin opening and downstream target genes were abrogated by inhibition of heparanase. Enhanced levels of heparanase in myeloma cells led to a dramatic increase in phosphorylation of PTEN, an event known to stabilize PTEN, leading to its inactivity and loss of tumor suppressor function. Collectively, this study demonstrates that heparanase promotes chromatin opening and transcriptional activity, some of which likely is through its impact on diminishing PTEN tumor suppressor activity.

scholarly journals Identification of a Novel E2F3 Product Suggests a Mechanism for Determining Specificity of Repression by Rb Proteins

2000 ◽  
Vol 20 (10) ◽  
pp. 3626-3632 ◽  
Author(s):  
Gustavo Leone ◽  
Faison Nuckolls ◽  
Seiichi Ishida ◽  
Monique Adams ◽  
Rosalie Sears ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Suppressor ◽  
Target Genes ◽  
Transcriptional Repressor ◽  
Tumor Suppressor Function ◽  
Proliferating Cells ◽  
Quiescent Cells ◽  
Suppressor Function ◽  
Intronic Promoter

ABSTRACT The tumor suppressor function of Rb is intimately related to its ability to interact with E2F and repress the transcription of E2F target genes. Here we describe a novel E2F product that specifically interacts with Rb in quiescent cells. This novel E2F, which we term E2F3b, is encoded by a unique mRNA transcribed from an intronic promoter within the E2F3 locus. The E2F3b RNA differs from the previously characterized E2F3 RNA, which we now term E2F3a, by the utilization of a unique coding exon. In contrast to the E2F3a product that is tightly regulated by cell growth, the E2F3b product is expressed equivalently in quiescent and proliferating cells. But, unlike the E2F4 and E2F5 proteins, which are also expressed in quiescent cells and form complexes with the p130 protein, the E2F3b protein associates with Rb and represents the predominant E2F-Rb complex in quiescent cells. Thus, the previously described specificity of Rb function as a transcriptional repressor in quiescent cells coincides with the association of Rb with this novel E2F product.

scholarly journals Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies

2017 ◽  
Vol 214 (10) ◽  
pp. 2901-2913 ◽  
Author(s):  
Tomoyuki Tanaka ◽  
Yaeko Nakajima-Takagi ◽  
Kazumasa Aoyama ◽  
Shiro Tara ◽  
Motohiko Oshima ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
T Lymphocyte ◽  
Transcriptional Activation ◽  
Lymphoblastic Leukemia ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Tumor Suppressor Function ◽  
Hematopoietic Stem ◽  
Suppressor Function ◽  
Exon 4

Recurrent inactivating mutations have been identified in various hematological malignancies in the X-linked BCOR gene encoding BCL6 corepressor (BCOR); however, its tumor suppressor function remains largely uncharacterized. We generated mice missing Bcor exon 4, expressing a variant BCOR lacking the BCL6-binding domain. Although the deletion of exon 4 in male mice (BcorΔE4/y) compromised the repopulating capacity of hematopoietic stem cells, BcorΔE4/y thymocytes had augmented proliferative capacity in culture and showed a strong propensity to induce acute T-cell lymphoblastic leukemia (T-ALL), mostly in a Notch-dependent manner. Myc, one of the critical NOTCH1 targets in T-ALL, was highly up-regulated in BcorΔE4/y T-ALL cells. Chromatin immunoprecipitation/DNA sequencing analysis revealed that BCOR was recruited to the Myc promoter and restrained its activation in thymocytes. BCOR also targeted other NOTCH1 targets and potentially antagonized their transcriptional activation. Bcl6-deficient thymocytes behaved in a manner similar to BcorΔE4/y thymocytes. Our results provide the first evidence of a tumor suppressor role for BCOR in the pathogenesis of T lymphocyte malignancies.

scholarly journals The HINT1 tumor suppressor regulates both γ-H2AX and ATM in response to DNA damage

2008 ◽  
Vol 183 (2) ◽  
pp. 253-265 ◽  
Author(s):  
Haiyang Li ◽  
Adayabalam S. Balajee ◽  
Tao Su ◽  
Bo Cen ◽  
Tom K. Hei ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Chromosomal Abnormalities ◽  
Cellular Responses ◽  
Suppressor Gene ◽  
Tumor Suppressor Function ◽  
Suppressor Function ◽  
Downstream Effectors ◽  
Induced Apoptosis

Hint1 is a haploinsufficient tumor suppressor gene and the underlying molecular mechanisms for its tumor suppressor function are unknown. In this study we demonstrate that HINT1 participates in ionizing radiation (IR)–induced DNA damage responses. In response to IR, HINT1 is recruited to IR-induced foci (IRIF) and associates with γ-H2AX and ATM. HINT1 deficiency does not affect the formation of γ-H2AX foci; however, it impairs the removal of γ-H2AX foci after DNA damage and this is associated with impaired acetylation of γ-H2AX. HINT1 deficiency also impairs acetylation of ATM and activation of ATM and its downstream effectors, and retards DNA repair, in response to IR. HINT1-deficient cells exhibit resistance to IR-induced apoptosis and several types of chromosomal abnormalities. Our findings suggest that the tumor suppressor function of HINT1 is caused by, at least in part, its normal role in enhancing cellular responses to DNA damage by regulating the functions of both γ-H2AX and ATM.

scholarly journals The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Beatriz Sanchez-Solana ◽  
Dunrui Wang ◽  
Xiaolan Qian ◽  
Parthibane Velayoudame ◽  
Dhirendra K. Simanshu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Structural Model ◽  
Suppressor Gene ◽  
Lipid Transfer ◽  
Tumor Suppressor Function ◽  
Suppressor Activity ◽  
Caveolin 1 ◽  
Suppressor Function ◽  
Start Domain

Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-START) domain, other than its binding to Caveolin-1, is poorly understood. In other START domains, a key function is that they bind lipids, but the putative lipid ligand for DLC1-START is unknown. Methods Lipid overlay assays and Phosphatidylserine (PS)-pull down assays confirmed the binding of DLC1-START to PS. Co-immunoprecipitation studies demonstrated the interaction between DLC1-START and Phospholipase C delta 1 (PLCD1) or Caveolin-1, and the contribution of PS to those interactions. Rho-GTP, cell proliferation, cell migration, and/or anchorage-independent growth assays were used to investigate the contribution of PS and PLCD1, or the implications of TCGA cancer-associated DLC1-START mutants, to DLC1 functions. Co-immunoprecipitations and PS-pull down assays were used to investigate the molecular mechanisms underlying the impaired functions of DLC1-START mutants. A structural model of DLC1-START was also built to better understand the structural implications of the cancer-associated mutations in DLC1-START. Results We identified PS as the lipid ligand for DLC1-START and determined that DLC1-START also binds PLCD1 protein in addition to Caveolin-1. PS binding contributes to the interaction of DLC1 with Caveolin-1 and with PLCD1. The importance of these activities for tumorigenesis is supported by our analysis of 7 cancer-associated DLC1-START mutants, each of which has reduced tumor suppressor function but retains wildtype RhoGAP activity. Our structural model of DLC1-START indicates the mutants perturb different elements within the structure, which is correlated with our experimental findings that the mutants are heterogenous with regard to the deficiency of their binding properties. Some have reduced PS binding, others reduced PLCD1 and Caveolin-1 binding, and others are deficient for all of these properties. Conclusion These observations highlight the importance of DLC1-START for the tumor suppressor function of DLC1 that is RhoGAP-independent. They also expand the versatility of START domains, as DLC1-START is the first found to bind PS, which promotes the binding to other proteins.

scholarly journals VHLSynthetic Lethality Signatures Uncovered by Genotype-specific CRISPR-Cas9 Screens

2019 ◽  
Author(s):  
Ning Sun ◽  
Sakina Petiwala ◽  
Charles Lu ◽  
Jessica E Hutti ◽  
Min Hu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Drug Targets ◽  
Target Genes ◽  
Synthetic Lethality ◽  
Suppressor Gene ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Genome Wide ◽  
Tumor Suppressor Gene Inactivation

AbstractBackgroundGenome-wide CRISPR-Cas9 essentiality screening represents a powerful approach to identify genetic vulnerabilities in cancer cells. Here, we applied this technology and designed a strategy to identify target genes that are synthetic lethal (SL) withvon Hippel-Lindau(VHL) tumor suppressor gene. Inactivation ofVHLhas been frequently found in clear cell renal cell carcinoma (ccRCC). Its SL partners serve as potential drug targets for the development of targeted cancer therapies.ResultsWe performed parallel genome-wide CRISPR screens in two pairs of isogenic ccRCC cell lines that differ only in theVHLstatus. Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as major SL targets inVHL-inactivated cancer cells. Follow-up studies provided cellular and mechanistic insights into SL interactions of these pathway genes with theVHLgene.ConclusionsUsing isogenic CRISPR screening approach, we uncovered novel biological processes that are SL withVHL, which can be exploited for drug development for ccRCC. Our CRISPR and RNA-seq datasets provide a rich resource for future investigation of the function of the VHL tumor suppressor protein. Our work demonstrates the efficiency of CRISPR-based synthetic lethality screening in human isogenic cell pairs. Similar strategies could be employed to unveil SL partners with other oncogenic drivers.

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