Molecular Pathogenesis of MDS

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 156-160 ◽  
Author(s):  
A. Thomas Look
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Suppressor Genes ◽  
Hematopoietic Stem ◽  
Chromosomal Deletions ◽  
Genes Encoding

Abstract Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q–, 5q–, 20q–, 6q–, 11q– and 13q–) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench1 and Fenaux2). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD.3 Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells,4 the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (α-catenin) and c/EBPα, and implicating these genes as tumor suppressors.5–7 Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q– and (del)5q.

A Mouse Model of Alkylator-Induced Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 368-368 ◽  
Author(s):  
Deepa Edwin ◽  
Christine McMahon ◽  
Friederike Kreisel ◽  
Molly Bogue ◽  
Timothy S. Fenske ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Mouse Model ◽  
Tumor Suppressor Genes ◽  
Bone Marrow Cells ◽  
Point Mutations ◽  
Comparative Genomic ◽  
Suppressor Genes ◽  
Hematopoietic Stem ◽  
Molecular Abnormalities ◽  
Key Features

Abstract The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and cellular dysplasia. Peripheral blood cytopenias and progression to AML are important clinical sequelae of MDS. 10–20% of MDS cases are a consequence of prior treatment with alkylators. The molecular basis of therapy-related MDS (t-MDS) is poorly understood. Point mutations of RAS family members and inactivation of the p53 and p15 tumor suppressor genes by mutation or hypermethylation represent the most frequently reported molecular abnormalities in MDS. Clonal cytogenetic changes, usually involving loss of material from chromosomes 5 and/or 7 are present in >90% of t-MDS cases. These recurring deletions suggest that myeloid tumor suppressor genes may be present in these regions, although their identify has not yet been established. Progress in understanding the genetic basis of human MDS has been hampered by a lack of suitable animal models. To develop a mouse model of t-MDS, we screened 32 inbred strains for susceptibility to t-MDS after treatment with the prototypical alkylating agent, N-nitroso-N-ethylurea (ENU). Mice (n=12 per strain) received two doses of ENU (100mg/kg, IP) or no treatment (n=12 per strain) at 9 and 10 weeks of age. Among the strains tested, SWR/J mice were found to be highly susceptible to myeloid malignancies (MDS/AML). We confirmed this in a second cohort. 10 of 33 (30%) ENU-treated SWR/J mice developed key features of MDS, including anemia (mean Hb=10.9 ±1.1 g/dL, compared to mean Hb=14.0 ±0.3 g/dL in 32 untreated age and sex-matched SWR/J mice, p=0.0006) and erythroid dysplasia (megaloblastic maturation, nuclear budding and blebbing in normoblasts) with a latency of approximately 30 weeks after ENU exposure. There was also evidence of dysplasia in the megakaryocytic lineage, manifested by numerous micromegakaryocytes with unilobar nuclei. Mild dysplastic features were detected rarely in untreated controls from this strain. The t-MDS mice developed significant splenomegaly (mean=0.49 ±0.19 g compared to control mean=0.15 ±0.01 g, p=0.004) with histologic evidence of increased extramedullary hematopoiesis. No significant immunophenotypic differences were detected in bone marrow cells from the t-MDS cases compared to controls. Iron stores were normal with no evidence of ringed sideroblasts. In 2 of the 10 affected mice, MDS evolved to AML, manifested by rapid breathing, circulating myeloid blasts, and leukocytosis (21-621,000 cells/μL). An additional 3 ENU-treated SWR/J mice developed AML without evidence of a preceding MDS phase. All AML cases had a Kit+Gr1+CD34- phenotype with no expression of lymphoid markers. The blasts were myeloperoxidase negative. This mouse model recapitulates many key features of human alkylator-associated t-MDS/AML and should be useful for discovery of mutations involved in the pathogenesis of this syndrome. We are employing array-based comparative genomic hybridization and candidate gene resequencing as tools for mutation discovery in this model. Because of their unique sensitivity to t-MDS, the SWR/J strain will also be particularly useful for identification of germline polymorphisms that affect susceptibility to alkylator-associated t-MDS/AML.

Methylation status of eight tumor suppressors in neuroendocrine pancreatic tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16197-e16197
Author(s):  
Oleg I. Kit ◽  
Vladimir S. Trifanov ◽  
Natalya N. Timoshkina ◽  
Dmitry Yu. Gvaldin ◽  
Milana Yu. Mesheryakova ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Blood Levels ◽  
Malignant Neoplasms ◽  
Gene Promoters ◽  
Suppressor Genes ◽  
Healthy Donors ◽  
Pancreatic Net

e16197 Background: Aberrant DNA methylation is a characteristic feature of cancer, affecting gene expression and tumor phenotype. In this study, we quantified the methylation of promoters of eight tumor suppressor genes in pancreatic neuroendocrine tumors (Pan-NET). Methods: The method of pyrosequencing was used to quantity level (Met,%) of methylation of gene promoters - tumor suppressors AHRR, APC1A, DAPK, MGMT, MLH1, P16, RASSF1A, RUNX3 in tumor samples from 55 patients with pancreatic NET (G1-G3) and in the blood of 10 healthy donors. Met for each sample was calculated as the median methylation of CpG sites in triplicate. Results: Hypermethylation was observed for AHRR (75%), APC1A (25%), RASSF1A (30%). In contrast, DAPK, MGMT, MLH1, P16, RUNX3 had low methylation levels ( < 20%). The median of methylation in the blood of healthy donors for AHRR was 91% (76-98); for all other loci it did not exceed 6%. A high incidence of methylation in excess of blood levels in healthy donors was identified for RASSF1A (0.96); AHRR (0.75); MGMT (0.65); RUNX3 (0.41), APC1A (0.25). For tumor suppressor P16, only one case of increased methylation was recorded (Met = 15%), despite the fact that this phenomenon is not uncommon for NETs of other localizations. In 66% of pancreatic NET cases, hypermethylation of more than two promoters of tumor suppressor genes was noted. An association tendency was found between the presence of MEN1 mutations and the RASSF1A methylation level (p = 0.08). Correlation analysis revealed a significant level of negative association between changes in methylation of MLH1 and AHRR (p < 0.01); for the latter, the prognostic value of a high methylation status and a better prognosis for many malignant neoplasms were described. Conclusions: In the present study, significant methylation of the promoters of the APC1A, DAPK, MGMT, RASSF1A, and RUNX3 genes in well-differentiated pancreatic NETs was identified with a high frequency. At the same time, isolated cases of hypermethylation were noted for the well-known tumor suppressors MLH1 and P16.

scholarly journals Inactivation of multiple tumor-suppressor genes involved in negative regulation of the cell cycle, MTS1/p16INK4A/CDKN2, MTS2/p15INK4B, p53, and Rb genes in primary lymphoid malignancies

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 4949-4958 ◽  
Author(s):  
A Hangaishi ◽  
S Ogawa ◽  
N Imamura ◽  
S Miyawaki ◽  
Y Miura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
Negative Regulators ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
Lymphoid Malignancies ◽  
Cell Cycle Machinery

It is now evident that the cell cycle machinery has a variety of elements negatively regulating cell cycle progression. However, among these negative regulators in cell cycle control, only 4 have been shown to be consistently involved in the development of human cancers as tumor suppressors: Rb (Retinoblastoma susceptibility protein), p53, and two recently identified cyclin-dependent kinase inhibitors, p16INK4A/MTS1 and p15INK4B/MTS2. Because there are functional interrelations among these negative regulators in the cell cycle machinery, it is particularly interesting to investigate the multiplicity of inactivations of these tumor suppressors in human cancers, including leukemias/lymphomas. To address this point, we examined inactivations of these four genes in primary lymphoid malignancies by Southern blot and polymerase chain reaction-single- strand conformation polymorphism analyses. We also analyzed Rb protein expression by Western blot analysis. The p16INK4A and p15INK4B genes were homozygously deleted in 45 and 42 of 230 lymphoid tumor specimens, respectively. Inactivations of the Rb and p53 genes were 27 of 91 and 9 of 173 specimens, respectively. Forty-one (45.1%) of 91 samples examined for inactivations of all four tumor suppressors had one or more abnormalities of these four tumor-suppressor genes, indicating that dysregulation of cell cycle control is important for tumor development. Statistical analysis of interrelations among impairments of these four genes indicated that inactivations of the individual tumor-suppressor genes might occur almost independently. In some patients, disruptions of multiple tumor-suppressor genes occurred; 4 cases with p16INK4A, p15INK4B, and Rb inactivations; 2 cases with p16INK4A, p15INK4B, and p53 inactivations; and 1 case with Rb and p53 inactivations. It is suggested that disruptions of multiple tumor suppressors in a tumor cell confer an additional growth advantage on the tumor.

scholarly journals Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma

Blood ◽  
2016 ◽  
Vol 128 (13) ◽  
pp. 1735-1744 ◽  
Author(s):  
Niels Weinhold ◽  
Cody Ashby ◽  
Leo Rasche ◽  
Shweta S. Chavan ◽  
Caleb Stein ◽  
...  
Keyword(s):  
High Risk ◽  
Tumor Suppressor ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Clonal Selection ◽  
Therapeutic Approaches ◽  
Apoptosis Resistance ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Key Points

Key PointsHits in driver genes and bi-allelic events affecting tumor suppressors increase apoptosis resistance and proliferation rate–driving relapse. Excessive biallelic inactivation of tumor suppressors in high-risk cases highlights the need for TP53-independent therapeutic approaches.

ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147

2018 ◽  
Author(s):  
Defang Zhou ◽  
Jingwen Xue ◽  
Pingping Zhuang ◽  
Xiyao Cui ◽  
Shuhai He ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanism ◽  
Tumor Suppressor Genes ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Tumor Formation ◽  
Signalling Pathway ◽  
Suppressor Genes ◽  
Pathway Crosstalk ◽  
Pathogenic Effects

AbstractThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV), as two oncogenic retroviruses, showed synergistic pathogenic effects characterized by enhanced tumor initiation and progression. The molecular mechanism underlying synergistic effects of ALV-J and REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and REV enhanced the ability of virus infection, increased viral life cycle, maintained cell survival and enhanced tumor formation. We combined the high-throughput proteomic readout with a large-scale miRNA screening to identify which molecules are involved in the synergism. Our results revealed co-infection of ALV-J and REV activated a latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. Our results contributed to the understanding of the molecular mechanisms of viral synergistic tumorgenesis, which provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes.Author summaryThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection with ALV-J and REV showed synergistic pathogenic effects characterized by enhanced tumor progression, however, the molecular mechanism on the neoplasia remains unclear. Our results revealed co-infection of ALV-J and REV promotes tumorigenesis by both induction of a latent oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-147. Mechanistic studies revealed that ALV-J and REV synergistically enhance KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. These results provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes, indicating the potential preventive target and predictive factor for ALV-J and REV induced tumorigenesis.

scholarly journals Macrophages, Inflammation, and Tumor Suppressors: ARF, a New Player in the Game

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Paqui G. Través ◽  
Alfonso Luque ◽  
Sonsoles Hortelano
Keyword(s):  
Tumor Suppressor ◽  
Immune Responses ◽  
Cancer Progression ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Macrophage Polarization ◽  
Innate Immune

The interaction between tumor progression and innate immune system has been well established in the last years. Indeed, several lines of clinical evidence indicate that immune cells such as tumor-associated macrophages (TAMs) interact with tumor cells, favoring growth, angiogenesis, and metastasis of a variety of cancers. In most tumors, TAMs show properties of an alternative polarization phenotype (M2) characterized by the expression of a series of chemokines, cytokines, and proteases that promote immunosuppression, tumor proliferation, and spreading of the cancer cells. Tumor suppressor genes have been traditionally linked to the regulation of cancer progression; however, a growing body of evidence indicates that these genes also play essential roles in the regulation of innate immunity pathways through molecular mechanisms that are still poorly understood. In this paper, we provide an overview of the immunobiology of TAMs as well as what is known about tumor suppressors in the context of immune responses. Recent advances regarding the role of the tumor suppressor ARF as a regulator of inflammation and macrophage polarization are also reviewed.

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