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Journal articles on the topic "RUNX2"
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Pulikkan, John Anto, Xue Liting, Rachel Gerstein, Merav Socolovsky, and Lucio H. Castilla. "Deletion Of Core Binding Factors Runx1 and Runx2 Leads To Perturbed Hematopoiesis In Multiple Lineages." Blood 122, no. 21 (November 15, 2013): 46. http://dx.doi.org/10.1182/blood.v122.21.46.46.
Full textAbstract:
The core binding factor (CBF) is a transcription factor that regulates key modulators of growth, survival and differentiation pathways. The CBF consists of a DNA binding α subunit (encoded by RUNX1, RUNX2, and RUNX3) and a common non-DNA binding β subunit (CBFB). RUNX1 and CBFB have been shown to be indispensible for embryo definitive hematopoiesis and to regulate adult hematopoiesis, and are targets of mutations in acute myeloid leukemia and myeloid dysplastic syndromes. We have shown that Runx2 is expressed in hematopoietic stem and early progenitor cells (HSPC: LSK+= Lin-ckit+Sca1+) and that it modulates leukemia latency in mice. However, little is known of Runx2 role in hematopoiesis. In this study, we have used conditional knock out mice for Runx1, Runx2, Runx1 and Runx2, and Cbfb (namely: Rx1ko, Rx2ko, Rx12dko, and Cbfbko) and the Cre deletors Mx1Cre and Vav-Cre, to show that Runx1 and Runx2 regulate hematopoietic lineage differentiation. Analysis of HSPCs 2 weeks post Mx1Cre induction, the HSCs (LSK+, FLT3-) were increased 4 fold in Rx1ko and Rx12dko mice, while the multipotential progenitors (MPPs:LSK+, FLT3+) of Rx12dko mice were expanded 5 fold. These data indicate that Runx1 regulates HSCs while both Runx factors regulate MPPs. The cell-intrinsic role of CBF factors in hematopoiesis was studied by evaluating the multilineage repopulation in competitive repopulation assay. To this end, recipient mice were transplanted 1:1 ratio of test (Rx1fl/fl, Rx2fl/fl, Rx1fl/flRx2fl/fl, or Cbfbfl/fl; each with Mx1Cre;CD45.2) and competitor (wt;CD45.1) bone marrow cells, treated with pIpC 4 weeks later, and analyzed every 4 weeks up to week 20 by flow cytometry. This analysis showed that Runx1 and Runx2 regulate differentiation in cell type specific manner. Runx1 and Runx2 have antagonistic functions in B cell lineage development, and Runx1 (but not Runx2) regulates T cell differentiation. The monocytes were not affected by the loss of Runx1 or Runx2, but were markedly reduced in the absence of both factors, suggesting that Runx1 and Runx2 may co-regulate monocyte development. The granulocytes (Mac1+Gr1+) were not affected in by Runx1 and/or Runx2, but were drastically reduced in Cbfb-null cells, suggesting that Runx3 could regulate granulocyte differentiation. The mechanism of HSPC regulation by Runx factors was studied by expression analysis of genes associated with HSC function. We have found that expression of adhesion molecules Alcam, Cx43 and Cxcr4 were deregulated in Rx1ko and Rx2ko HSCs and MPPs, as well as self-renewal factors, including Cdkn1a, Gfi1 and Mpl. To assess whether these alterations would impair the retention of HSPCs in the niche, we tested the ability of HSPCs to recover from cytotoxic stress, using 5-fluorouracil. At day 7, the percentage of immature (c-kit+) cells in peripheral blood had returned to normal in Rx1ko, Rx2ko, and wt mice. However, Rx12dko mice showed a 15-20 fold increase in circulating immature (c-kit+) cells. In addition, the administration of a second 5-fluorouracil dose at day 14 induced hematopoietic exhaustion and death in wt, Rx1ko and Rx2ko mice, but Rx12dko mice survived and recovered. These experiments indicate that loss of both Runx factors impairs the adhesion of HSCs to the niche and re-establishment of HSPC homeostasis To further study the role of CBF factors in hematopoiesis, we analyzed lineage contribution in Cbfbfl/fl, Vav-Cre mice at week 8 after birth. The HSPCs (LSKs) were increased 10 fold in Cbfb-null mice. These mice presented pancytopenia, with a 2-fold reduction in white blood cell count and anemia. The erythroid lineage was affected, including reduction of megakaryocyte/erythroid progenitors and Ter119+ progenitor cells in bone marrow, and reduction of red blood cell count and hematocrit in peripheral blood. The peripheral blood T and B cells were also reduced 6 and 2 fold respectively. In the myeloid compartment, the granulocyte/monocyte progenitor cells were increased 2 fold in bone marrow, and granulocytes increased 3 fold in peripheral blood. These studies reveal that Runx1 and Runx2 transcription factors regulate expression of adhesion and self-renewal genes in the HSPC compartment, modulating the homeostasis of HSCs in the bone marrow niche. In addition, Runx1 and Runx2 regulate hematopoiesis differentiation by synergistic and opposing effects in lineage specific manner. Disclosures: No relevant conflicts of interest to declare.
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Estecio, Marcos R., Sirisha Maddipoti, Courtney D. DiNardo, Hui Yang, William S. Stevenson, Carlos E. Bueso-Ramos, Sherry R. Pierce, Yue Wei, and Guillermo Garcia-Manero. "Association Between RUNX3 Hypermethylation and Acute Myeloid Leukemia Inv(16) Subtype." Blood 124, no. 21 (December 6, 2014): 3548. http://dx.doi.org/10.1182/blood.v124.21.3548.3548.
Full textAbstract:
Abstract The RUNX family of transcription factors forms the DNA binding α-chain partners of the heterodimeric core binding factor (CBF) complex. Each of the RUNX proteins, RUNX1, RUNX2, and RUNX3, can form heterodimers with CBFβ. In the M4Eo subtype of human acute leukemia, the chromosomal translocation resulting in inversion 16 encodes a chimeric protein in which CBFβ is fused to smooth muscle myosin heavy chain (SMMHC). Although the exact mechanism of leukemogenesis by this chimera is unknown, it is thought that CBFβ-SMMHC sequesters RUNX1 in the cytoplasm and antagonizes its normal function. Although the role of RUNX1 in hematopoiesis has been previously well-established, recent data have indicated that the RUNX3 gene may also play a key role in the development of human acute leukemias. To clarify the role of RUNX3 in acute myeloid leukemia (AML), we investigated its expression and promoter DNA methylation in leukemia cell lines and patient samples. Eleven human leukemia cell lines of myeloid origin and twelve of lymphoid origin were used in this study. Cell suspensions from bone marrow aspirate specimens from patients with AML (69 cases), MDS (19 cases) and ALL (6 cases) were obtained prior to therapy from established tissue blocks. Peripheral blood samples were obtained from four healthy volunteers, and CD34+ cells were obtained from another four individuals. Methylation status of the gene promoters of RUNX1, RUNX2 and RUNX3 were evaluated using the Pyrosequencing Methylation Assay (PMA) method, and expression of RUNX3 was analyzed by quantitative real-time PCR and immunohistochemical staining. Hypermethylation of RUNX1 and RUNX2 was rare in cell lines; RUNX1 was not hypermethylated in any of the studied samples, and RUNX2 was hypermethylated in only two cell lines. In contrast, we found that the RUNX3 promoter was hypermethylated in 17 of the cell lines (74%). Interestingly, we observed a trend toward higher frequency of hypermethylation of RUNX3 in cell lines of myeloid (90%) compared to lymphoid (57%) origin. In patient samples, RUNX3 promoter methylation was below 15% in normal samples, and hypermethylation was found in 32/69 AML samples (46%), 4/19 MDS samples (21%), and 6/6 ALL samples (100%). Of the 69 AML samples, 19 were classified as AML M4Eo, and 50 were other types of AML. 84% of the human AML M4Eo samples were hypermethylated at the RUNX3 promoter region, whereas only 34% of the other AML subtypes were hypermethylated. We also evaluated DNA methylation of RUNX1 and RUNX2 in a subgroup of these samples (66 samples for RUNX1 and 72 for RUNX2) and found that, as in cell lines, these genes are almost universally unmethylated; with the exception of a single AML case, all studied samples presented no promoter methylation. As support of functional outcome, hypermethylation of RUNX3 was correlated with both lower levels of mRNA and protein, as confirmed by qRT-PCR and immunohistochemistry analysis in cell lines and patient samples, and treatment with the DNA demethylating agent Decitabine resulted in mRNA re-expression of RUNX3 concomitantly with decreased promoter methylation. Finally, we compared clinicopathological features of patients with and without RUNX3 methylation. In this analysis, only non-M4Eo AML cases were compared because of the small number of non-methylated patients in the M4Eo group. Differences were found neither for blood counts nor for overall survival probability. However, relapse-free survival was significantly better for the unmethylated group (p=0.016). In summary, we showed that promoter methylation of the RUNX3 gene and down regulation of RUNX3 expression occurs almost universally in M4Eo/inversion 16 AMLs, and that in cell lines, RUNX3 repression can be reversed by treatment with the hypomethylating agent decitabine. These results suggest that silencing of RUNX3 is likely an important target in CBF leukemia and that future studies should be dedicated to further characterize the role of RUNX3 in inversion 16 AML and its predictive value of relapse-free survival in AML. Disclosures No relevant conflicts of interest to declare.
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Morita, Ken, Kensho Suzuki, Shintaro Maeda, Yoshihide Mitsuda, Ayaka Yano, Yoshimi Yamada, Hiroki Kiyose, et al. "Cluster Regulation of RUNX Family By "Gene Switch" Triggers a Profound Tumor Regression of Diverse Origins." Blood 128, no. 22 (December 2, 2016): 443. http://dx.doi.org/10.1182/blood.v128.22.443.443.
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Abstract Although Runt-related transcription factor 1 (RUNX1), a member of RUNX family and a distant relative of p53, has been generally considered to be a tumor suppressor, a growing body of evidence strongly suggests its pro-oncogenic property in acute myeloid leukemia (AML). Here we demonstrate that switching off RUNX cluster utilizing the newly synthesized compound, which specifically bound to a particular base sequence of DNA, was highly effective against leukemia as well as dismal-prognostic solid tumors arising from diverse origins in vivo. Firstly, to assess the RUNX1 loss in AML cells, we performed shRNA-mediated RUNX1 knockdown experiments. Silencing of RUNX1 stimulated cell cycle arrest at G0/G1 phase and simultaneously induced apoptosis in AML cells bearing wild-type p53. RUNX1 depletion induced remarkable induction of p53 as well as its target gene products and additive knockdown of p53 in these cell lines reverted the phenotype of RUNX1-depletion, indicating that RUNX1 is functionally dependent on proficient p53 pathway. In addition, cycloheximide chase assay revealed that RUNX1 negatively regulates p53 protein in AML cells. In silico data analysis of clinical gene expression array data sets and ChIP-seq experiments using anti-RUNX1 antibody identified 32 candidate genes potentially required for RUNX1-dependent degradation of p53. Among them, we focused on BCL11A and TRIM24, both of which are established mediators of p53 degradation. In accordance with these observations, knockdown of RUNX1 resulted in a significant down-regulation of BCL11A and TRIM24 both at mRNA and protein levels. ChIP-qPCR assay further validated the actual binding of RUNX1 at the promoter regions of these genes, and reintroduction of BCL11A or TRIM24 into RUNX1-silenced AML cells restored their proliferation speed to the control levels. These data suggests that RUNX1 depletion-mediated growth inhibitory effect on leukemia cells depends on p53 activation via transcriptional regulation of BCL11A and TRIM24. Though RUNX1 depletion was highly effective on proliferation of AML cells, a small sub-population of leukemia cells retained the proliferation potential even after the silencing of RUNX1. Since it has been shown that RUNX family member has a redundant function, we next examined the other RUNX family members such as RUNX2 and RUNX3 in RUNX1-knocked down AML cells. Under our tetracycline-inducible shRNA expression system, the expression levels of RUNX1-target genes were decreased at 24 h after RUNX1 knockdown, however, their expression levels were reciprocally increased at 48 h accompanied by increment of RUNX2 and RUNX3 expressions, suggesting that RUNX2 and RUNX3 might compensate for the loss of RUNX1 functions. ChIP-qPCR assay and luciferase reporter experiments confirmed that individual RUNX family member consistently suppressed the promoter activity of the other RUNX members. In accordance with these findings, additional knockdown of RUNX2, RUNX3 or both of them in RUNX1-depleted AML cells effectively repressed RUNX1-target gene expressions and completely suppressed their proliferation. Thus the simultaneous targeting of all RUNX family members as a cluster achieves more stringent control of leukemia cells. Since sequencing analysis of the functional gene alterations of RUNX family members revealed the existence of mutations in a mutual-exclusive manner not only in AML cells but also in various cancers, their functional redundancy in the maintenance of AML cells might be generally accepted. To achieve cluster regulations of RUNX, we conducted a synthesized molecule library screening and succeeded in extracting agents that could irreversibly block the RUNX cluster genes expression profiling through dismantling protein-DNA interactions sequence-specifically. These reagents were highly effective against leukemia as well as dismal-prognostic solid tumors arising from diverse origins in vitro. Furthermore, these reagents were exceptionally well-tolerated in mice and exerted excellent efficacy against xenograft mice models of AML, acute lymphoblastc leukemia, lung and gastric cancers, extending their overall survival periods in vivo. Together, this work identifies the crucial role of RUNX cluster in the maintenance and the progression of cancer cells, and the indicated gene switch technology-dependent its modulation would be a novel strategy to control malignancies. Disclosures No relevant conflicts of interest to declare.
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Zhao, Ling, Jennifer L. Cannons, Lucio H. Castilla, Pamela L. Schwartzberg, and Pu Paul Liu. "The Role of CBFβ in T Cell Development." Blood 104, no. 11 (November 16, 2004): 3234. http://dx.doi.org/10.1182/blood.v104.11.3234.3234.
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Abstract Core binding factor β (Cbfβ) is a transcription factor that heterodimerizes with Runx (Cbfα) family members, thereby stabilizing the interaction between the Runx proteins and DNA. Genetically manipulated mouse models of Runx and Cbfb genes have demonstrated their critical functions in hematopoiesis (Runx1, Runx3 and Cbfb), bone formation (Runx2, Cbfb), proliferation of gastrointestinal epithelia (Runx3) and differentiation of dorsal root ganglion cells (Runx3). Studies on T cell development showed that Runx1 and Runx3 repress CD4 expression at different stages of development. In addition, Runx 1 and Runx 3 are required for CD8 T cell development during thymopoiesis. No defects were found when Runx2 was inactivated, even though it is expressed throughout T cell development. We have previously generated a knock-in mouse model expressing the Cbfb-MYH11 fusion gene (which is created by inv(16)(p13; q22) in human AML M4Eo). Heterozygous knock-in mice had a phenotype identical to that of the Cbfb and Runx1 null mice (embryonic lethality), suggesting that the fusion gene Cbfb-MYH11 functions in a dominant-negative manner. In order to study the function of Cbfb gene in T cell development, we used a mouse line with floxed exons 5 and 6 of Cbfb inserted 5′ to the Cbfb-MYH11 fusion cassette, which produced pseudo-normal mice (loxKI). By crossing the loxKI mice with mice expressing the Cre gene under the control of the T cell-specific Lck promoter (LckCre), we generated LckCre-loxKI double positive mice, in which the floxed exon 5 and 6 were deleted and Cbfb-MYH11 re-expressed only in the thymus when Lck started to express. The LckCre-loxKI mice were viable. However, their thymic development was severely impaired: The size of the thymuses in the mutant mice was about half the normal size, and the total number of thymocytes in the mutant mice was 10–20-fold reduced. FACS analysis of thymocytes from 4 to 12 week old mice showed a developmental blockade at the CD4/CD8-double negative (DN) stage, which was characterized by lower percentage of double positive cells and higher percentage of double negative cells. In addition, the CD4: CD8 ratio was altered. Furthermore, the mature T cell population size in the spleen of the mutant mice was lower than that of the control mice. Our preliminary data suggested that Cbfb plays an important role in T cell development. The mechanism through which Cbfb affects the T cell development is currently under investigation. It is likely that the phenotype reflects the combined effect of missing all three Runx genes, since the phenotype described here is more severe than either Runx1 or Runx3 null alone.
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Zhao, Yangli, Tingjuan Zhang, Yangjing Zhao, and Jingdong Zhou. "Distinct association of RUNX family expression with genetic alterations and clinical outcome in acute myeloid leukemia." Cancer Biomarkers 29, no. 3 (October 28, 2020): 387–97. http://dx.doi.org/10.3233/cbm-200016.
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BACKGROUND: The runt-related transcription factor family (RUNXs) including RUNX1, RUNX2, and RUNX3 are key transcriptional regulators in normal hematopoiesis. RUNXs dysregulations caused by aberrant expression or mutation are frequently seen in various human cancers especially in acute myeloid leukemia (AML). OBJECTIVE: We systemically analyzed the expression of RUNXs and their relationship with clinic-pathological features and prognosis in AML patients. METHODS: Expression of RUNXs was analyzed between AML patients and normal controls from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) projects. Correlations between RUNXs expression and clinical features together with survival were further analyzed. RESULTS: All RUNXs expression in AML patients was significantly increased as compared with controls. RUNXs expression was found to be significantly associated with genetic abnormalities such as RUNX1 mutation, t(8;21) and inv(16)/t(16;16). By Kaplan-Meier analysis, only RUNX3 overexpression was associated with shorter overall survival (OS) and disease-free survival (DFS) among non-M3 AML patients. Notably, in high RUNX3 expression groups, patients received hematopoietic stem cell transplantation (HSCT) had markedly better OS and DFS than patients without HSCT among both all AML and non-M3 AML. In low RUNX3 expression groups, there were no significant differences in OS and DFS between HSCT and non-HSCT groups among both all AML and non-M3 AML. In addition, a total of 835 differentially expressed genes and 69 differentially expressed microRNAs were identified to be correlated with RUNX3 expression in AML. CONCLUSION: RUNXs overexpression was a frequent event in AML, and was closely associated with diverse genetic alterations. Moreover, RUNX3 expression may be associated with clinical outcome, and helpful for guiding treatment choice between HSCT and chemotherapy in AML.
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Maddipoti, Sirisha C., Carlos Bueso-Ramos, Hui Yang, Michael Fernandez, Shaoquing Kuang, Zihong Fang, William Stevenson, Yue Wei, Sherry Pierce, and Guillermo Garcia-Manero. "Epigenetic Silencing of the RUNX3 Gene by Promoter Hypermethylation in Patients with Acute Myeloid Leukemia." Blood 112, no. 11 (November 16, 2008): 3341. http://dx.doi.org/10.1182/blood.v112.11.3341.3341.
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Abstract The RUNX family of transcription factors forms the DNA binding α-chain partner of the heterodimeric core binding factor (CBF) complex. Each of the RUNX proteins, RUNX1 (AML1), RUNX2, and RUNX3 (AML2), can form heterodimers with CBFβ. While the role of RUNX1 in hematopoiesis has previously been well established, recent data have indicated that the RUNX3 gene may also play a key role in the development of human acute leukemias. RUNX3 promoter hypermethylation and downregulation of gene expression have been shown in human gastric and lung cancers, indicative of its function as a tumor suppressor gene. Prior cDNA gene expression arrays of acute myeloid leukemia have noted a downregulation of RUNX3 gene expression in blast cells of inversion 16 AML M4 Eo, with no evidence for somatic mutations in this gene. We therefore wanted to analyze the promoter methylation status of RUNX3 in patients with inversion 16 AML. Using bisulfite treatment of DNA, PCR amplification of the RUNX3 promoter, and pyrosequencing analysis, we initially studied 23 leukemia cell lines. We found that the RUNX3 promoter was hypermethylated at 17 of 23 cell lines, using a cutoff of >15% for hypermethylation, with a mean methylation percentage of 43 and a range of 4–97 (median 31%). We subsequently analyzed RUNX3 gene expression levels in eight of the leukemia cell lines by real-time PCR and were able to demonstrate low baseline expression, with reexpression after treatment with the hypomethylating agent decitabine. We also showed a decrease in percentage methylation of the RUNX3 promoter after treating three of the cell lines with decitabine. We then determined the methylation profile of 81 patients with acute myeloid leukemia (median age 65 [20–84], median WBC at presentation 10 [0.7–114], median percent of marrow blasts 52 [8–94], cytogenetics: inv16 22 (25%), t(8;21) 4 (4%), diploid 23 (27%), the rest abnormal). We observed that 21 of 22 AML M4 Eo samples (95%) were hypermethylated at RUNX3, with a mean methylation percentage of 50 and a range of 4.5–98 (median 49%). Of the other AML subtypes, 20 of 59 patient samples (33%) were hypermethylated, with a mean methylation of 23%, and range of 1–79 (median 12.5%). The RUNX3 promoter was unmethylated in four CD34+ normal controls, and six peripheral blood controls. No correlation between RUNX3 methylation and prognosis was detected in the non inv16 AML cases. Immunohistochemistry performed on the AML M4 Eo bone marrow specimens confirmed the presence of the core-binding factor chimeric protein. We also studied six ALL patient samples and all six were hypermethylated at the RUNX3 promoter, with a mean methylation of 30%, and a range of 21–39 (median 31%). Finally, 19 MDS samples were studied: only four were hypermethylated with an average of 10.5%, and a range of 2.5–47 (median 6.1%). We also analyzed the methylation profile of the RUNX1 and RUNX2 genes on the leukemia cell lines, AML, ALL, and MDS patient samples, and normal controls. The RUNX1 and RUNX2 promoters were universally unmethylated. Our results indicate that epigenetic dysregulation of RUNX3 is likely an important target in the molecular pathway of leukemogenesis in core binding factor leukemia.
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Cheng, Chi Keung, Libby Li, Suk Hang Cheng, Kin Mang Lau, Natalie P. H. Chan, Raymond S. M. Wong, Matthew M. K. Shing, Chi Kong Li, and Margaret H. L. Ng. "Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia." Blood 112, no. 8 (October 15, 2008): 3391–402. http://dx.doi.org/10.1182/blood-2008-02-137083.
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Abstract RUNX3/AML2 is a Runt domain transcription factor like RUNX1/AML1 and RUNX2/AML3. Regulated by 2 promoters P1 and P2, RUNX3 is frequently inactivated by P2 methylation in solid tumors. Growing evidence has suggested a role of this transcription factor in hematopoiesis. However, genetic alterations have not been reported in blood cancers. In this study on 73 acute myeloid leukemia (AML) patients (44 children and 29 adults), we first showed that high RUNX3 expression among childhood AML was associated with a shortened event-free survival, and RUNX3 was significantly underexpressed in the prognostically favorable subgroup of AML with the t(8;21) and inv(16) translocations. We further demonstrated that this RUNX3 repression was mediated not by P2 methylation, but RUNX1-ETO and CBFβ-MYH11, the fusion products of t(8;21) and inv(16), via a novel transcriptional mechanism that acts directly or indirectly in collaboration with RUNX1, on 2 conserved RUNX binding sites in the P1 promoter. In in vitro studies, ectopically expressed RUNX1-ETO and CBFβ-MYH11 also inhibited endogenous RUNX3 expression. Taken together, RUNX3 was the first transcriptional target found to be commonly repressed by the t(8;21) and inv(16) fusion proteins and might have an important role in core-binding factor AML.
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de Bruijn, Marella, and Elaine Dzierzak. "Runx transcription factors in the development and function of the definitive hematopoietic system." Blood 129, no. 15 (April 13, 2017): 2061–69. http://dx.doi.org/10.1182/blood-2016-12-689109.
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AbstractThe Runx family of transcription factors (Runx1, Runx2, and Runx3) are highly conserved and encode proteins involved in a variety of cell lineages, including blood and blood-related cell lineages, during developmental and adult stages of life. They perform activation and repressive functions in the regulation of gene expression. The requirement for Runx1 in the normal hematopoietic development and its dysregulation through chromosomal translocations and loss-of-function mutations as found in acute myeloid leukemias highlight the importance of this transcription factor in the healthy blood system. Whereas another review will focus on the role of Runx factors in leukemias, this review will provide an overview of the normal regulation and function of Runx factors in hematopoiesis and focus particularly on the biological effects of Runx1 in the generation of hematopoietic stem cells. We will present the current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopoietic function.
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McKillop, Anne Jane, Joanne Edwards, Emma Johnson, Susan Mason, Ewan R. Cameron, and Karen Blyth. "Investigating RUNX1 and RUNX2 in prostate cancer." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 232. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.232.
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232 Background: Prostate cancer is the most commonly diagnosed cancer in men and is increasing in incidence. Current treatment for metastatic disease is initially hormone treatment and chemotherapy. While this produces a response in the vast majority of patients, it is not curative. Novel therapeutic agents could provide a further treatment strategy and it is therefore important to understand the molecular pathways which contribute to this disease. The RUNX family of genes have been implicated as both oncogenes and tumor suppressors, with their role being context dependent. It has been reported that RUNX2 may have a tumor suppressor role in early stage prostate cancer but that this may switch to an oncogenic role in later stage disease. Methods: This project examines the expression of both RUNX1 and RUNX2 in a tissue microarray (TMA) of human prostate cancers. In parallel to the human studies both RUNX1 and RUNX2 were investigated in murine models of prostate cancer. Results: Analysis of the TMA showed that increasing levels of RUNX2 were associated with increasing Gleason grade, shorter time to relapse and poorer survival; the opposite effect was seen in RUNX1, where low levels of protein expression correlated with shorter survival. In concordance with the human results, reducing levels of RUNX2 in mouse models was associated with delayed tumor initiation, and smaller, less cystic tumors at endpoint. The opposite effect was seen with Runx1 where low levels resulted in more aggressive and invasive disease. Finally, when loss of both genes was combined in a model with loss of Pten and stimulation of WNT, survival was significantly reduced compared to controls. Conclusions: This study suggests that RUNX2 expression may correlate with a poorer prognosis in prostate cancer, while expression of RUNX1 is likely to be associated with an improved outcome.
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Wang, X. P., T. Åberg, M. J. James, D. Levanon, Y. Groner, and I. Thesleff. "Runx2 (Cbfa1) Inhibits Shh Signaling in the Lower but not Upper Molars of Mouse Embryos and Prevents the Budding of Putative Successional Teeth." Journal of Dental Research 84, no. 2 (February 2005): 138–43. http://dx.doi.org/10.1177/154405910508400206.
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Heterozygous mutations in the RUNX2 ( CBFA1) gene cause cleidocranial dysplasia, characterized by multiple supernumerary teeth. This suggests that Runx2 inhibits successional tooth formation. However, in Runx2 knockout mice, molar development arrests at the late bud stage, and lower molars are more severely affected than upper ones. We have proposed that compensation by Runx3 may be involved. We compared the molar phenotypes of Runx2/Runx3 double-knockouts with those of Runx2 knockouts, but found no indication of such compensation. Shh and its mediators Ptc1, Ptc2, and Gli1 were down-regulated only in the lower but not the upper molars of Runx2 and Runx2/Runx3 knockouts. Interestingly, in front of the mutant upper molar, a prominent epithelial bud protruded lingually with active Shh signaling. Similar buds were also present in Runx2 heterozygotes, and they may represent the extension of dental lamina for successional teeth. The results suggest that Runx2 prevents the formation of Shh-expressing buds for successional teeth.
Dissertations / Theses on the topic "RUNX2"
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Yamamoto, Hiromitsu. "Runx2 and Runx3 are essential for chondrocyte maturation and Runx2 regulates limb growth through induction of Indian hedgehog." Kyoto University, 2004. http://hdl.handle.net/2433/145283.
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Schäfer, Henning Sebastian. "Die Untersuchung des Transkriptionsfaktors RUNX2, insbesondere die RUNX2-Cbfß Interaktion in der Pathogenese der cleidocranialen Dysplasie." [S.l. : s.n.], 2005.
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Stephens, Alexandre, and N/A. "Genetic and Functional Characterization of RUNX2." Griffith University. School of Medical Science, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070823.100953.
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RUNX2 belongs to the RUNT domain family of transcription factors of which three have been identified in humans (RUNX1, RUNX2 and RUNX3). RUNX proteins are vital for metazoan development and participate in the regulation of cellular differentiation and cell cycle progression (Coffman, 2003). RUNX2 is required for proper bone formation by driving the differentiation of osteoblasts from mesenchymal progenitors during development (Ducy et al, 1997; Komori et al, 1997; Otto et al, 1997). RUNX2 is also vital for chondrocyte maturation by promoting the differentiation of chondrocytes to the hypertrophic phenotype (Enomoto et al, 2000). The consequences of completely disrupting the RUNX2 locus in mice provided compelling and conclusive evidence for the biological importance of RUNX2 where knockout mice died shortly after birth with a complete lack of bone formation (Komori et al, 1997; Otto et al, 1997). A further indication of the requisite role of RUNX2 in skeletal development was the discovery that RUNX2 haploinsufficiency in humans and mice caused the skeletal syndrome Cleidocranial Dysplasia (CCD) (Mundlos et al, 1997; Lee et al, 1997). A unique feature of RUNX2 is the consecutive polyglutamine and polyalanine tracts (Q/A domain). Mutations causing CCD have been observed in the Q/A domain of RUNX2 (Mundlos et al, 1997). The Q/A domain is an essential part of RUNX2 and participates in transactivation function (Thirunavukkarasu et al, 1998). Previous genotyping studies conducted in our laboratory identified several rare RUNX2 Q/A variants in addition to a frequently occurring 18 base pair deletion of the polyalanine tract termed the 11Ala allele. Analysis of serum parameters in 78 Osteoarthritis patients revealed the 11Ala allele was associated with significantly decreased osteocalcin. Furthermore, analysis of 11Ala allele frequencies within a Geelong Osteoporosis Study (GOS) fracture cohort and an appropriate age matched control group revealed the 11Ala allele was significantly overrepresented in fracture cases indicating an association with increased fracture risk. To further investigate the 11Ala allele and rare Q/A variants, 747 DNA samples from the Southeast Queensland bone study were genotyped using PCR and PAGE. The experiment served two purposes: 1) to detect additional rare Q/A variants to enrich the population of already identified mutants and 2) have an independent assessment of the effect of the 11Ala allele on fracture to either support or refute our previous observation which indicated the 11Ala allele was associated with an increased risk of fracture in the GOS. From the 747 samples genotyped, 665 were WT, 76 were heterozygous for the 11Ala allele, 5 were homozygous for the 11Ala allele and 1 was heterozygous for a rare 21 bp deletion of the polyglutamine tract. Chi-square analysis of RUNX2 genotype distributions within fracture and non-fracture groups in the Southeast Queensland bone study revealed that individuals that carried at least one copy of the 11Ala allele were enriched in the fracture group (p = 0.16, OR = 1.712). The OR of 1.712 was of similar magnitude to the OR observed in the GOS case-control investigation (OR = 1.9) providing support for the original study. Monte-Carlo simulations were used to combine the results from the GOS and the Southeast Queensland bone study. The simulations were conducted with 10000 iterations and demonstrated that the maximum probability of obtaining both study results by chance was less than 5 times in two hundred (p < 0.025) suggesting that the 11Ala allele of RUNX2 was associated with an increased fracture risk. The second element of the research involved the analysis of rare RUNX2 Q/A variants identified from multiple epidemiological studies of bone. Q/A repeat variants were derived from four populations: the GOS, an Aberdeen cohort, CAIFOS and a Sydney twin study. Collectively, a total of 20 rare glutamine and one alanine variants were identified from 4361 subjects. All RUNX2 Q/A variants were heterozygous for a mutant allele and a wild type allele. Analysis of incident fracture during a five year follow up period in the CAIFOS revealed that Q-variants (n = 8) were significantly more likely to have fractured compared to non-carriers (p = 0.026, OR 4.932 95% CI 1.2 to 20.1). Bone density data as measured by quantitative ultrasound was available for CAIFOS. Analysis of BUA and SOS Z-scores revealed that Q-repeat variants had significantly lower BUA (p = 0.031, mean Z-score of -0.79) and a trend for lower SOS (p = 0.190, mean Z-score of -0.69). BMD data was available for all four populations. To normalize the data across the four studies, FN BMD data was converted into Z-scores and the effect of the Q/A variants on BMD was analysed using a one sample approach. The analysis revealed Q/A variants had significantly lower FN BMD (p = 0.0003) presenting with a 0.65 SD decrease. Quantitative transactivation analysis was conducted on RUNX2 proteins harbouring rare glutamine mutations and the 11Ala allele. RUNX2 proteins containing a glutamine deletion (16Q), a glutamine insertion (30Q) and the 11Ala allele were overexpressed in NIH3T3 and HEK293 cells and their ability to transactivate a known target promoter was assessed. The 16Q and 30Q had significantly decreased reporter activity compared to WT in NIH3T3 cells (p = 0.002 and 0.016, for 16Q and 30Q, respectively). In contrast 11Ala RUNX2 did not show significantly different promoter activation potential (p = 0.54). Similar results were obtained in HEK293 cells where both the 16Q and 30Q RUNX2 displayed decreased reporter activity (p=0.007 and 0.066 for 16Q and 30Q respectively) whereas the 11Ala allele had no material effect on RUNX2 function (p = 0.20). The RUNX2 gene target reporter assay provided evidence to suggest that variation within the glutamine tract of RUNX2 was capable of altering the ability of RUNX2 to activate a known target promoter. In contrast, the 11Ala allele showed no variation in RUNX2 activity. The third feature of the research served the purpose of identifying potential RUNX2 gene targets with particular emphasis on discovering genes cooperatively regulated by RUNX2 and the powerful bone promoting agent BMP2. The experiment was conducted by creating stably transfected NIH3T3 cells lines overexpressing RUNX2 or BMP2 or both RUNX2 and BMP2. Microarray analysis revealed very few genes were differentially regulated between standard NIH3T3 cells and cells overexpressing RUNX2. The results were confirmed via RT-PCR analysis which demonstrated that the known RUNX2 gene targets Osteocalcin and Matrix Metalloproteinase-13 were modestly induced 2.5 fold (p = 0.00017) and 2.1 fold (p = 0.002) respectively in addition to identifying only two genes (IGF-II and SCYA11) that were differentially regulated greater than 10 fold. IGF-II and SYCA11 were significantly down-regulated 27.6 fold (p = 1.95 x 10-6) and 10.1 fold (p = 0.0002) respectively. The results provided support for the notion that RUNX2 on its own was not sufficient for optimal gene expression and required the presence of additional factors. To discover genes cooperatively regulated by RUNX2 and BMP2, microarray gene expression analysis was performed on standard NIH3T3 cells and NIH3T3 cells stably transfected with both RUNX2 and BMP2. Comparison of the gene expression profiles revealed the presence of a large number of differentially regulated genes. Four genes EHOX, CCL9, CSF2 and OSF-1 were chosen to be further characterized via RT-PCR. Sequential RT-PCR analysis on cDNA derived from control cells and cells stably transfected with either RUNX2, BMP2 or both RUNX2/BMP2 revealed that EHOX and CSF2 were cooperatively induced by RUNX2 and BMP2 whereas CCL9 and OSF-1 were suppressed by BMP2. The overexpression of both RUNX2 and BMP2 in NIH3T3 fibroblasts provided a powerful model upon which to discover potential RUNX2 gene targets and also identify genes synergistically regulated by BMP2 and RUNX2. The fourth element of the research investigated the role of RUNX2 in the ascorbic acid mediated induction of MMP-13 mRNA. The study was carried out using NIH3T3 cell lines stably transfected with BMP2, RUNX2 and both BMP2 and RUNX2. The cell lines were grown to confluence and subsequently cultured for a further 12 days in standard media or in media supplemented with AA. RT-PCR analysis was used to assess MMP-13 mRNA expression. The RT-PCR results demonstrated that AA was not sufficient for inducing MMP-13 mRNA in NIH3T3 cells. In contrast RUNX2 significantly induced MMP-13 levels 85 fold in the absence of AA (p = 0.0055) and upregulated MMP-13 mRNA levels 254 fold in the presence of AA (p = 0.0017). The results demonstrated that RUNX2 was essential for the AA mediated induction of MMP-13 mRNA in NIH3T3 cells. The effect of BMP2 on MMP-13 expression was also investigated. BMP2 induced MMP-13 mRNA transcripts a modest 3.8 fold in the presence of AA (p = 0.0027). When both RUNX2 and BMP2 were overexpressed in the presence of AA, MMP-13 mRNA levels were induced a massive 4026 fold (p = 8.7 x 10-4) compared to control cells. The investigation revealed that RUNX2 was an essential factor for the AA mediated induction of MMP-13 and that RUNX2 and BMP2 functionally cooperated to regulate MMP-13 mRNA levels.
4
Stephens, Alexandre. "Genetic and Functional Characterization of RUNX2." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/365677.
Full textAbstract:
RUNX2 belongs to the RUNT domain family of transcription factors of which three have been identified in humans (RUNX1, RUNX2 and RUNX3). RUNX proteins are vital for metazoan development and participate in the regulation of cellular differentiation and cell cycle progression (Coffman, 2003). RUNX2 is required for proper bone formation by driving the differentiation of osteoblasts from mesenchymal progenitors during development (Ducy et al, 1997; Komori et al, 1997; Otto et al, 1997). RUNX2 is also vital for chondrocyte maturation by promoting the differentiation of chondrocytes to the hypertrophic phenotype (Enomoto et al, 2000). The consequences of completely disrupting the RUNX2 locus in mice provided compelling and conclusive evidence for the biological importance of RUNX2 where knockout mice died shortly after birth with a complete lack of bone formation (Komori et al, 1997; Otto et al, 1997). A further indication of the requisite role of RUNX2 in skeletal development was the discovery that RUNX2 haploinsufficiency in humans and mice caused the skeletal syndrome Cleidocranial Dysplasia (CCD) (Mundlos et al, 1997; Lee et al, 1997). A unique feature of RUNX2 is the consecutive polyglutamine and polyalanine tracts (Q/A domain). Mutations causing CCD have been observed in the Q/A domain of RUNX2 (Mundlos et al, 1997). The Q/A domain is an essential part of RUNX2 and participates in transactivation function (Thirunavukkarasu et al, 1998). Previous genotyping studies conducted in our laboratory identified several rare RUNX2 Q/A variants in addition to a frequently occurring 18 base pair deletion of the polyalanine tract termed the 11Ala allele. Analysis of serum parameters in 78 Osteoarthritis patients revealed the 11Ala allele was associated with significantly decreased osteocalcin. Furthermore, analysis of 11Ala allele frequencies within a Geelong Osteoporosis Study (GOS) fracture cohort and an appropriate age matched control group revealed the 11Ala allele was significantly overrepresented in fracture cases indicating an association with increased fracture risk. To further investigate the 11Ala allele and rare Q/A variants, 747 DNA samples from the Southeast Queensland bone study were genotyped using PCR and PAGE. The experiment served two purposes: 1) to detect additional rare Q/A variants to enrich the population of already identified mutants and 2) have an independent assessment of the effect of the 11Ala allele on fracture to either support or refute our previous observation which indicated the 11Ala allele was associated with an increased risk of fracture in the GOS. From the 747 samples genotyped, 665 were WT, 76 were heterozygous for the 11Ala allele, 5 were homozygous for the 11Ala allele and 1 was heterozygous for a rare 21 bp deletion of the polyglutamine tract. Chi-square analysis of RUNX2 genotype distributions within fracture and non-fracture groups in the Southeast Queensland bone study revealed that individuals that carried at least one copy of the 11Ala allele were enriched in the fracture group (p = 0.16, OR = 1.712). The OR of 1.712 was of similar magnitude to the OR observed in the GOS case-control investigation (OR = 1.9) providing support for the original study. Monte-Carlo simulations were used to combine the results from the GOS and the Southeast Queensland bone study. The simulations were conducted with 10000 iterations and demonstrated that the maximum probability of obtaining both study results by chance was less than 5 times in two hundred (p < 0.025) suggesting that the 11Ala allele of RUNX2 was associated with an increased fracture risk. The second element of the research involved the analysis of rare RUNX2 Q/A variants identified from multiple epidemiological studies of bone. Q/A repeat variants were derived from four populations: the GOS, an Aberdeen cohort, CAIFOS and a Sydney twin study. Collectively, a total of 20 rare glutamine and one alanine variants were identified from 4361 subjects. All RUNX2 Q/A variants were heterozygous for a mutant allele and a wild type allele. Analysis of incident fracture during a five year follow up period in the CAIFOS revealed that Q-variants (n = 8) were significantly more likely to have fractured compared to non-carriers (p = 0.026, OR 4.932 95% CI 1.2 to 20.1). Bone density data as measured by quantitative ultrasound was available for CAIFOS. Analysis of BUA and SOS Z-scores revealed that Q-repeat variants had significantly lower BUA (p = 0.031, mean Z-score of -0.79) and a trend for lower SOS (p = 0.190, mean Z-score of -0.69). BMD data was available for all four populations. To normalize the data across the four studies, FN BMD data was converted into Z-scores and the effect of the Q/A variants on BMD was analysed using a one sample approach. The analysis revealed Q/A variants had significantly lower FN BMD (p = 0.0003) presenting with a 0.65 SD decrease. Quantitative transactivation analysis was conducted on RUNX2 proteins harbouring rare glutamine mutations and the 11Ala allele. RUNX2 proteins containing a glutamine deletion (16Q), a glutamine insertion (30Q) and the 11Ala allele were overexpressed in NIH3T3 and HEK293 cells and their ability to transactivate a known target promoter was assessed. The 16Q and 30Q had significantly decreased reporter activity compared to WT in NIH3T3 cells (p = 0.002 and 0.016, for 16Q and 30Q, respectively). In contrast 11Ala RUNX2 did not show significantly different promoter activation potential (p = 0.54). Similar results were obtained in HEK293 cells where both the 16Q and 30Q RUNX2 displayed decreased reporter activity (p=0.007 and 0.066 for 16Q and 30Q respectively) whereas the 11Ala allele had no material effect on RUNX2 function (p = 0.20). The RUNX2 gene target reporter assay provided evidence to suggest that variation within the glutamine tract of RUNX2 was capable of altering the ability of RUNX2 to activate a known target promoter. In contrast, the 11Ala allele showed no variation in RUNX2 activity. The third feature of the research served the purpose of identifying potential RUNX2 gene targets with particular emphasis on discovering genes cooperatively regulated by RUNX2 and the powerful bone promoting agent BMP2. The experiment was conducted by creating stably transfected NIH3T3 cells lines overexpressing RUNX2 or BMP2 or both RUNX2 and BMP2. Microarray analysis revealed very few genes were differentially regulated between standard NIH3T3 cells and cells overexpressing RUNX2. The results were confirmed via RT-PCR analysis which demonstrated that the known RUNX2 gene targets Osteocalcin and Matrix Metalloproteinase-13 were modestly induced 2.5 fold (p = 0.00017) and 2.1 fold (p = 0.002) respectively in addition to identifying only two genes (IGF-II and SCYA11) that were differentially regulated greater than 10 fold. IGF-II and SYCA11 were significantly down-regulated 27.6 fold (p = 1.95 x 10-6) and 10.1 fold (p = 0.0002) respectively. The results provided support for the notion that RUNX2 on its own was not sufficient for optimal gene expression and required the presence of additional factors. To discover genes cooperatively regulated by RUNX2 and BMP2, microarray gene expression analysis was performed on standard NIH3T3 cells and NIH3T3 cells stably transfected with both RUNX2 and BMP2. Comparison of the gene expression profiles revealed the presence of a large number of differentially regulated genes. Four genes EHOX, CCL9, CSF2 and OSF-1 were chosen to be further characterized via RT-PCR. Sequential RT-PCR analysis on cDNA derived from control cells and cells stably transfected with either RUNX2, BMP2 or both RUNX2/BMP2 revealed that EHOX and CSF2 were cooperatively induced by RUNX2 and BMP2 whereas CCL9 and OSF-1 were suppressed by BMP2. The overexpression of both RUNX2 and BMP2 in NIH3T3 fibroblasts provided a powerful model upon which to discover potential RUNX2 gene targets and also identify genes synergistically regulated by BMP2 and RUNX2. The fourth element of the research investigated the role of RUNX2 in the ascorbic acid mediated induction of MMP-13 mRNA. The study was carried out using NIH3T3 cell lines stably transfected with BMP2, RUNX2 and both BMP2 and RUNX2. The cell lines were grown to confluence and subsequently cultured for a further 12 days in standard media or in media supplemented with AA. RT-PCR analysis was used to assess MMP-13 mRNA expression. The RT-PCR results demonstrated that AA was not sufficient for inducing MMP-13 mRNA in NIH3T3 cells. In contrast RUNX2 significantly induced MMP-13 levels 85 fold in the absence of AA (p = 0.0055) and upregulated MMP-13 mRNA levels 254 fold in the presence of AA (p = 0.0017). The results demonstrated that RUNX2 was essential for the AA mediated induction of MMP-13 mRNA in NIH3T3 cells. The effect of BMP2 on MMP-13 expression was also investigated. BMP2 induced MMP-13 mRNA transcripts a modest 3.8 fold in the presence of AA (p = 0.0027). When both RUNX2 and BMP2 were overexpressed in the presence of AA, MMP-13 mRNA levels were induced a massive 4026 fold (p = 8.7 x 10-4) compared to control cells. The investigation revealed that RUNX2 was an essential factor for the AA mediated induction of MMP-13 and that RUNX2 and BMP2 functionally cooperated to regulate MMP-13 mRNA levels.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Faculty of Health
Full Text
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Fitzgerald, Mark. "Evidence For The Involvement Of Runx1 And Runx2 In Maintenance Of The Breast Cancer Stem Cell Phenotype." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/888.
Full textAbstract:
In the United States, metastatic breast cancer kills approximately 40,000 women and 400 men annually, and approximately 200,000 new cases of breast cancer are diagnosed each year. Worldwide, breast cancer is the leading cause of cancer deaths among women. Despite advances in the detection and treatment of metastatic breast cancer, mortality rates from this disease remain high because the fact is that once metastatic, it is virtually incurable. It is widely accepted that a major reason breast cancer continues to exhibit recurrence after remission is that current therapies are insufficient for targeting and eliminating therapy-resistant cancer cells. Emerging research has demonstrated that these therapy-resistant cells possess stem cell-like properties and are therefore commonly referred to as breast cancer stem cells (BCSCs). A major hallmark of BCSCs is the cell surface expression of CD44 and lack of expression of CD24, the so-called CD24-/CD44+ phenotype. Research indicates that this dangerous and rare subpopulation of BCSCs may be responsible for cancer onset, recurrence, and ultimately metastasis that leads to death.
Two different model systems were utilized in this research. The first was the MCF7 cell line, a luminal A tumor subtype representative of a mildly invasive breast ductal carcinoma with an ER+/PR+/-/HER2- immunoprofile. The second was the MCF10A breast cancer progression model, which consists of three cell lines: MCF10A, MCF10AT1, and MCF10CA1a. In this system, spontaneously immortalized, non-malignant MCF10A cells were transfected with constitutively active H-Ras to form pre-malignant MCF10AT1 cells, which were then subcutaneously injected into mice and allowed to metastasize in order to form the oncogenic MCF10ACA1a cell line.
This thesis presents evidence of a CD24low/-/CD44+ BCSC subpopulation within the MCF10A breast cancer progression model system. Findings indicate that RUNX1 and RUNX2 expression levels are involved in maintaining the BCSC phenotype. Across two different model systems, qRT-PCR analysis revealed that decreased levels of RUNX1 expression and increased levels of RUNX2 expression are essential for the maintenance of the BCSC subpopulation. It was also shown that low expression levels of RUNX1 and high expression levels of RUNX2 are present in CD24low/-/CD44+ BCSCs as compared to CD24+/CD44+ non-BCSCs. Furthermore, shRNA knockdown of RUNX1 was shown to enhance tumorigenicity, while shRNA knockdown of RUNX2 repressed tumorigenicity in BCSCs, as measured by the tumorsphere-formation assay. This research lays the groundwork for future investigations into the roles of RUNX1 and RUNX2 in regulating stemness in breast cancer.
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Vega, Villa Óscar Andrés. "RUNX2 promueve la progresión tumor en osteosarcoma." Tesis, Universidad de Chile, 2011. http://repositorio.uchile.cl/handle/2250/170931.
Full textAbstract:
Magíster en ciencias médicas, mención biología celularEl Osteosarcoma (OS) es el tumor sólido maligno más frecuente en la infancia y la adolescencia, corresponde al 20% de todos los tumores óseos y al 5% de los cánceres pediátricos. Los tratamientos actuales logran tasas de sobrevida a 5 años de 75% en pacientes sin metástasis, mientras que el 80% de los pacientes con enfermedad metastásica recaen a pesar del tratamiento efectuado. Runx2 es un factor de transcripción maestro que regula el proceso de diferenciación osteogénica, aunque este factor también promueve progresión tumoral en células de cáncer de próstata y de mama. Recientemente, se demostró la amplificación del gen Runx2 en pacientes con OS, así como la expresión aumentada de la proteína Runx2 en líneas celulares de OS. En esta tesis se propuso la hipótesis que el factor de transcripción Runx2 promueve migración e invasión en líneas celulares de osteosarcoma. Así, el objetivo general del proyecto fue definir el rol de Runx2 en los procesos de progresión tumoral en osteosarcoma. Para estudiar el rol de Runx2 sobre parámetros de progresión tumoral en líneas celulares de osteosarcoma, se moduló la expresión de Runx2 y se estudió su efecto en migración e invasividad. Nuestros resultados muestran que la sobreexpresión de Runx2 mediante adenovirus produjo un aumento en la capacidad de migración e invasión de líneas celulares de OS con bajos niveles de Runx2. El silenciamiento de Runx2 mediante siRNA disminuyó la capacidad de migración e invasión en líneas celulares de OS. De esta forma, hemos demostrado por primera vez que Runx2 promueve progresión tumoral en líneas celulares de OS.
Osteosarcoma (OS) is the most common malignant solid tumor in childhood and adolescence and represents 20% of all bone tumors and 5% of childhood cancers. Survival rates after five years are at 75% in patients without metastases, while 80% of patients with metastatic disease relapse despite the treatment. Runx2 is a master transcription factor that regulates the osteogenic differentiation process. However, this factor also functions as tumor promoter in prostate cancer cells and breast cancer. Runx2 gene amplification in patients with OS, as well as increased expression of Runx2 protein in OS cell line have recently been demonstrated. To this project, we hypothesized that the transcription factor Runx2 promotes migration and invasion in OS cell lines. Thus, the general aim was to define the role of Runx2 in osteosarcoma tumor progression processes. To study the role of Runx2 on parameters involved in tumor progression of OS cell lines, we modulated the expression of Runx2 and studied the outcome of this modifications on cell migration and invasiveness. Our results demonstrated that overexpression of Runx2 by adenovirus in OS cell lines with low levels of Runx2 increased cell migration and invasion. Runx2 silencing by siRNA in OS cell lines decreased their ability to migrate and invade. Thus, we have demonstrated for the first time that Runx2 promotes tumor progression in OS cell lines.
7
Brown, Jessie Ann. "RUNX2 in Embryonic Heart Development and Heart Disease." Thesis, The University of Arizona, 2011. http://hdl.handle.net/10150/144250.
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Gersbach, Charles Alan. "Runx2-Genetically Engineered Skeletal Myoblasts for Bone Tissue Engineering." Diss., Georgia Institute of Technology, 2006. http://hdl.handle.net/1853/11600.
Full textAbstract:
Bone tissue engineering is a promising approach to address the limitations of currently used bone tissue substitutes. However, an optimal cell source for the production of osteoblastic matrix proteins and mineral deposition has yet to be defined. In response to this deficiency, ex vivo gene therapy of easily accessible non-osteogenic cells, such as skeletal myoblasts, has become a prevalent strategy for inducing an osteoblastic phenotype. The majority of these approaches focus on constitutive overexpression of soluble osteogenic growth factors such as bone morphogenetic proteins (BMPs). In order to avoid aberrant effects of unregulated growth factor secretion, this work focuses on delivery of the osteoblastic transcription factor Runx2 as an autocrine osteogenic signal under the control of an inducible expression system. The overall objective of this research was to engineer an inducible cell source for bone tissue engineering that addresses the limitations of current cell-based approaches to orthopedic regeneration. Our central hypothesis was that inducible Runx2 overexpression in skeletal myoblasts would stimulate differentiation into a regulated osteoblastic phenotype. We have demonstrated that Runx2 overexpression stimulates transdifferentiation of primary skeletal myoblasts into a mineralizing osteoblastic phenotype. Furthermore, we have established Runx2-engineered skeletal myoblasts as a potent cell source for bone tissue engineering applications in vitro and in vivo, similar to BMP-2-overexpressing controls. Finally, we exogenously regulated osteoblastic differentiation by myoblasts engineered to express a tetracycline-inducible Runx2 transgene. This conversion into an osteoblastic phenotype was inducible, repressible, recoverable after suppression, and dose-dependent with tetracycline concentration. This work is significant because it addresses cell sourcing limitations of bone tissue engineering, develops controlled and effective gene therapy methods for orthopedic regeneration, and establishes a novel strategy for regulating the magnitude and kinetics of osteoblastic differentiation.
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Phillips, Jennifer Elizabeth. "Runx2-Genetically Engineered Dermal Fibroblasts for Orthopaedic Tissue Repair." Diss., Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/19818.
Full textAbstract:
Tissue engineering has emerged as a promising alternative to conventional orthopaedic grafting therapies. The general paradigm for this approach, in which phenotype-specific cells and/or bioactive growth factors are integrated into polymeric matrices, has been successfully applied in recent years toward the development of bone, ligament, and cartilage tissues in vitro and in vivo. Despite these advances, an optimal cell source for skeletal tissue repair and regeneration has not been identified. Furthermore, the lack of robust, functional orthopaedic tissue interfaces, such as the bone-ligament enthesis, severely limits the integration and biological performance of engineered tissue substitutes. This works aims to address these limitations by spatially controlling the genetic modification and differentiation of fibroblasts into a mineralizing osteoblastic phenotype within three-dimensional polymeric matrices. The overall objective of this project was to investigate transcription factor-based gene therapy strategies for the differentiation of fibroblasts into a mineralizing cell source for orthopaedic tissue engineering applications. Our central hypothesis was that fibroblasts genetically engineered to express Runx2 via conventional and biomaterial-mediated ex vivo gene transfer approaches will differentiate into a mineralizing osteoblastic phenotype. We have demonstrated that a combination of retroviral Runx2 overexpression and glucocorticoid hormone treatment synergistically induces osteoblastic differentiation and biological mineral deposition in primary dermal fibroblasts cultured in monolayer. We report for the first time that glucocorticoids induce osteoblastic differentiation in this model system by modulating the phosphorylation state of a negative regulatory serine residue (Ser125) on Runx2 through an MKP-1-dependent mechanism. Furthermore, we utilized these Runx2-genetically engineered fibroblasts to create mineralized templates for bone repair in vitro and in vivo. Finally, we engineered a heterogeneous bone-soft tissue interface with a novel biomaterial-mediated gene transfer approach. Overall, these results are significant toward the ultimate goal of regenerating complex, higher-order orthopaedic grafting templates which mimic the cellular and microstructural characteristics of native tissue. Cellular therapies based on primary dermal fibroblasts would be particularly beneficial for patients with a compromised ability to recruit progenitors to the sight of injury as result of traumatic injury, radiation treatment, or osteodegenerative disease.
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Doecke, James. "Genetic variation in Runx2 related to bone mineral density." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367841.
Full textAbstract:
The main hypotheses tested within this research focussed on the identification of polymorphisms within Runx2, and the classification of these with respect to bone mineral density (BMD). A separate set of hypotheses focussed upon the effects of calcium treatment in an elderly population, to identify any differences in BMD, bone mineral content (BMC) and bone area between the specific genotypes identified. The initial research strategy included taking subjects’ from the extremes of a population to identify alleles specifically related to the bone mineral density trait. The idea was tested using Runx2, the well known osteoblast transcription factor. From a population of 1300 subjects (from the Geelong Osteoporosis Study: the GOS) the age-weight adjusted femoral neck BMD was ranked and the upper and lower deciles taken to represent the adjusted extremes. After adjusting and ranking, the two groups (n=130 each) were not significantly different for age or weight. In these 260 subjects, we identified 16 allelic variations within the Runx2 gene and gene promoters (P1 and P2), and characterized these novel variations with respect to BMD strata by genotype using DHPLC.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Books on the topic "RUNX2"
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Shimazu, Junko. Regulation of Runx2 Accumulation and Its Consequences. [New York, N.Y.?]: [publisher not identified], 2016.
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2
Groner, Yoram, Yoshiaki Ito, Paul Liu, James C. Neil, Nancy A. Speck, and Andre van Wijnen, eds. RUNX Proteins in Development and Cancer. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2.
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Ito, Yoshiaki, Paul Liu, and Yoram Groner. RUNX Proteins in Development and Cancer. Springer, 2017.
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Ito, Yoshiaki, Paul Liu, Yoram Groner, James C. Neil, and Nancy A. Speck. RUNX Proteins in Development and Cancer. Springer, 2017.
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Ito, Yoshiaki, Paul Liu, Yoram Groner, James C. Neil, Nancy A. Speck, and Andre van Wijnen. RUNX Proteins in Development and Cancer. Ingramcontent, 2017.
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Ito, Yoshiaki, Paul Liu, Yoram Groner, James C. Neil, Nancy A. Speck, and Andre van Wijnen. RUNX Proteins in Development and Cancer. Springer, 2018.
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Lillard, Rossilyn. Too Scared To Run2: Loss Of Fear, Victim Turned Vigilante. CreateSpace Independent Publishing Platform, 2017.
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8
Djuretic, Ivana. Regulation of gene expression in T lymphocytes by the transcription factor Runx3. 2009.
Find full textBook chapters on the topic "RUNX2"
1
Komori, Toshihisa. "Roles of Runx2 in Skeletal Development." In Advances in Experimental Medicine and Biology, 83–93. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_6.
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Komori, Toshihisa. "Regulation of Osteoblast Differentiation by Runx2." In Advances in Experimental Medicine and Biology, 43–49. Boston, MA: Springer US, 2009. http://dx.doi.org/10.1007/978-1-4419-1050-9_5.
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Brusgard, Jessica L., and Antonino Passaniti. "RUNX2 Transcriptional Regulation in Development and Disease." In Nuclear Signaling Pathways and Targeting Transcription in Cancer, 57–86. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-8039-6_3.
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Greenblatt, Matthew B., Jae-Hyuck Shim, Weiguo Zou, and Laurie H. Glimcher. "A Tak1/p38 Signaling Axis Regulates Runx2 Activity and Osteoblast Functions." In Osteoimmunology, 49–56. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4614-5366-6_6.
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Pulica, Rachael, Karine Cohen-Solal, and Ahmed Lasfar. "Evaluating the Role of RUNX2 in Cancer and Its Potential as a Therapeutic Target." In Handbook of Cancer and Immunology, 1–22. Cham: Springer International Publishing, 2022. http://dx.doi.org/10.1007/978-3-030-80962-1_254-1.
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Shiraha, Hidenori, Shigeru Horiguchi, and Hiroyuki Okada. "RUNX3." In Encyclopedia of Signaling Molecules, 4781–86. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101799.
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Moore, Amy C. "Runx1." In Encyclopedia of Cancer, 1–5. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. http://dx.doi.org/10.1007/978-3-642-27841-9_5131-2.
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Shiraha, Hidenori, Shigeru Horiguchi, and Hiroyuki Okada. "RUNX3." In Encyclopedia of Signaling Molecules, 1–5. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101799-1.
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Moore, Amy C. "Runx1." In Encyclopedia of Cancer, 4104–9. Berlin, Heidelberg: Springer Berlin Heidelberg, 2016. http://dx.doi.org/10.1007/978-3-662-46875-3_5131.
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Moore, Amy C. "Runx1." In Encyclopedia of Cancer, 3322–26. Berlin, Heidelberg: Springer Berlin Heidelberg, 2011. http://dx.doi.org/10.1007/978-3-642-16483-5_5131.
Full textConference papers on the topic "RUNX2"
1
Okoli, Uzoamaka A. "Abstract PO-150: Comparison of RUNX1, RUNX2, RUNX3 and CBFβ gene expression in breast tumors Indicate ethnic differences and similarities by receptor status." In Abstracts: AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; October 6-8, 2021. American Association for Cancer Research, 2022. http://dx.doi.org/10.1158/1538-7755.disp21-po-150.
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Gnanamony, Manu, Indra Mohanam, and Sanjeeva Mohanam. "Abstract 499: RUNX2 protects human neuroblastoma cells against apoptosis." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-499.
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Sase, Tomohiko, Takashi Suzuki, Kou Miura, Yoshiaki Onodera, Ryuichirou Sato, Hideaki Karasawa, Akihiro Yamamura, et al. "Abstract 2235: Immunohistochemical analysis of RUNX2 in human colon cancer." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-2235.
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Shikata, Tetsuo, Toshihiko Shiraishi, Shin Morishita, and Ryohei Takeuchi. "Effects of Acceleration Amplitude and Frequency of Mechanical Vibration on Cultured Osteoblasts." In ASME 2008 International Mechanical Engineering Congress and Exposition. ASMEDC, 2008. http://dx.doi.org/10.1115/imece2008-67221.
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This paper describes the effects of the frequency and acceleration amplitude of mechanical vibration on osteoblasts, the bone cells that generate the bone matrix. Their cell proliferation and bone matrix generation were investigated when sinusoidal inertia force was applied to the cells. Bone formation is subject in vivo to mechanical stimulation. Although many researches for bone cells of osteoblastic lineage sensing and responding to mechanical stimulation have been reported mainly in the biochemical field, effects of mechanical stimulation on bone cells are not well understood. After the cells were cultured in culture plates in a CO2 incubator for one day and adhered on the cultured plane, vibrating groups of the culture plates were set on an aluminum plate attached to a exciter and cultured under sinusoidal excitation in another incubator separated from non-vibrating groups of the culture plates. Acceleration amplitude and frequency were set to several kinds of conditions. The time evolution of cell density was obtained by counting the number of cells with a hemocytometer. Calcium salts generated by the cells were observed by being stained with alizarin red S solution and their images were captured with a CCD camera. The vibrating groups for the cell proliferation and the calcium salts staining were sinusoidally excited for 24 hours a day during 28 days of culture. Gene expression of alkaline phosphatase (ALP) and runt-related gene 2 (Runx2) was measured by a real-time reverse transcription polymerase chain reaction (real-time RT-PCR) method. After the vibrating groups for the PCR were excited for 4 days, the total RNAs were extracted. After reverse transcription, real-time RT-PCR was performed. Gene expression for ALP, Runx2, and a housekeeping gene were determined simultaneously for each sample. ALP and Runx2 gene level in each sample was normalized to the measured housekeeping gene level. The following experimental results of sinusoidal excitation of osteoblasts have been shown: (a) Cell density decreased at 0.5 G with increasing frequency in the range from 12.5 to 1000 Hz and increased at 25 Hz with increasing acceleration amplitude from 0 to 0.5 G at 14 days of culture. (b) No calcium salts were observed in the non-vibrating group and the areas of calcium salts observed in the 0.5 G vibration group were larger than those in the 0.25 G group at 25 Hz at 21 days of culture. (c) The mRNA level of ALP at 0.5 G showed the peak at 50 Hz in the range from 12.5 to 1000 Hz and that at 50 Hz showed the peak at 0.5 G in the range from 0.25 to 1 G at 4 days of culture. In the case of Runx2, the same tendency was found. It has been shown that it is important to consider mechanical vibration as well as biochemical aspects in studies of the functional adaptation of cells to mechanical stimulation.
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Gnanamony, Manu, Indra Mohanam, and Sanjeeva Mohanam. "Abstract 5213: RUNX2 modulates the angiogenic potential of human neuroblastoma cells." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5213.
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Roos, Alison, Jason T. Yustein, and Larry Donehower. "Abstract 5036: Oncogenic role of Runx2 in the development of osteosarcoma." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5036.
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Majid, Shahana, Hanna Nip, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yozo Mitsui, et al. "Abstract 1619: MicroRNA-466 regulates bone metastasis by targeting RUNX2 in prostate cancer." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-1619.
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Xiaoying Liu and Yuguang Gao. "Runx2 is involved in regulating amelotin promoter activity and gene expression in ameloblasts." In 2013 ICME International Conference on Complex Medical Engineering (CME 2013). IEEE, 2013. http://dx.doi.org/10.1109/iccme.2013.6548218.
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Othman, Ahmad, Marcus Winogradzki, Manish Tandon, and Jitesh Pratap. "Abstract 1240: Runx2 promotes microtubule stability for survival of breast cancer bone metastatic cells." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-1240.
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Garzón-Alvarado, D. A., and L. M. Peinado-Cortés. "Appearance and Development of Secondary Ossification Center: A Mathematical Model Approach." In ASME 2010 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2010. http://dx.doi.org/10.1115/sbc2010-19648.
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This paper introduces an “hypothesis about the growth pattern of the secondary ossification centre (SOC)”, whereby two phases are assumed. First, the formation of cartilage canals as an event essential for the development of the SOC. Second, hence the canals are merged in the central zone of the epiphysis, molecular factors are released (primarily Runx2 and MMP9) spreading and causing hypertrophy of adjacent cells. In order to test this hypothesis we solve a system of coupled partial differential equations using the finite element method and we have obtained spatio-temporal patterns of the growth process of the SOC. The model is in qualitatively agreement with experimental results previously reported by other authors.
Reports on the topic "RUNX2"
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Franceschi, Renny T. Epigenetic Control of Prostate Cancer Metastasis: Role of Runx2 Phosphorylation. Fort Belvoir, VA: Defense Technical Information Center, April 2013. http://dx.doi.org/10.21236/ada580104.
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Franceschi, Renny T. Epigenetic Control of Prostate Cancer Metastasis: Role of Runx2 Phosphorylation. Fort Belvoir, VA: Defense Technical Information Center, May 2015. http://dx.doi.org/10.21236/ada620609.
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