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Pulikkan, John Anto, Xue Liting, Rachel Gerstein, Merav Socolovsky i Lucio H. Castilla. "Deletion Of Core Binding Factors Runx1 and Runx2 Leads To Perturbed Hematopoiesis In Multiple Lineages". Blood 122, nr 21 (15.11.2013): 46. http://dx.doi.org/10.1182/blood.v122.21.46.46.
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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 i Guillermo Garcia-Manero. "Association Between RUNX3 Hypermethylation and Acute Myeloid Leukemia Inv(16) Subtype". Blood 124, nr 21 (6.12.2014): 3548. http://dx.doi.org/10.1182/blood.v124.21.3548.3548.
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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 i in. "Cluster Regulation of RUNX Family By "Gene Switch" Triggers a Profound Tumor Regression of Diverse Origins". Blood 128, nr 22 (2.12.2016): 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 i Pu Paul Liu. "The Role of CBFβ in T Cell Development." Blood 104, nr 11 (16.11.2004): 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 i Jingdong Zhou. "Distinct association of RUNX family expression with genetic alterations and clinical outcome in acute myeloid leukemia". Cancer Biomarkers 29, nr 3 (28.10.2020): 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 i Guillermo Garcia-Manero. "Epigenetic Silencing of the RUNX3 Gene by Promoter Hypermethylation in Patients with Acute Myeloid Leukemia." Blood 112, nr 11 (16.11.2008): 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 i 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, nr 8 (15.10.2008): 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, i Elaine Dzierzak. "Runx transcription factors in the development and function of the definitive hematopoietic system". Blood 129, nr 15 (13.04.2017): 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 i Karen Blyth. "Investigating RUNX1 and RUNX2 in prostate cancer." Journal of Clinical Oncology 35, nr 6_suppl (20.02.2017): 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 i 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, nr 2 (luty 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.
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Suzuki, Kensho, Ken Morita, Shintaro Maeda, Hiroki Kiyose, Souichi Adachi i Yasuhiko Kamikubo. "Paradoxical Enhancement of Leukemogenesis in Acute Myeloid Leukemia Cells with Moderately Attenuated RUNX1 Expressions". Blood 128, nr 22 (2.12.2016): 2710. http://dx.doi.org/10.1182/blood.v128.22.2710.2710.
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Abstract Although Runt-related transcription factor 1 (RUNX1), a member of RUNX transcription family, is known for its oncogenic role in the development of acute myeloid leukemia (AML), evidence from other groups support the oncosuppressive property of RUNX1 in leukemia cells, casting a question over the bidirectional function of RUNX1 and it is currently highly controversial. Here we report that the dual function of RUNX1 possibly arise from the total level of RUNX family expressions. To examine the precise mechanism of RUNX1 expression in leukemogenesis, we first prepared several tetracycline-inducible short hairpin RNAs (shRNAs) which could attenuate the expressions of RUNX1 at different levels in AML cells (MV4-11 and MOLM-13 cells). Intriguingly, while AML cells transduced with shRNAs which could down-regulate RUNX1 expression below 10% at protein level (sh_Rx1_profound) deteriorated the proliferation speed of AML cells, AML cells transduced with shRNAs which could moderately down-regulate RUNX1 expression to 70% at protein level (sh_Rx1_moderate) paradoxically promoted the cell cycle progression and doubled the growth rate of AML cells. Besides, RUNX1-moderately expressing AML patient cohort exhibited the worse outcome compared to RUNX1-high or RUNX1-low expressing cohorts (n = 187), indicating an underlying mechanism that confer growth advantage to AML cells with moderately inhibited RUNX1 expressions. To further investigate the correspondent gene in this paradoxical enhancement of oncogenesis in sh_Rx1_moderate-transduced AML cells, we performed comprehensive gene expression array and extracted genes that are highly up-regulated in RUNX1 moderate inhibition and down-regulated in AML cells transduced with sh_Rx1_profound. We hereafter focused on the top-listed gene glutathione S-transferase alpha 2 (GSTA2) and addressed the interaction of RUNX1 and GSTA2 and their functions in AML cells. Real time quantitative PCR (RT-qPCR) and immunoblotting revealed that the expression of GSTA2 was actually up-regulated in sh_Rx1_moderate-transduced AML cells and down-regulated in AML cells transduced with sh_Rx1_profound. Interestingly, equivalent level of compensatory up-regulation of RUNX2 and RUNX3 were observed in sh_Rx1_moderate- and sh_Rx1_profound-transduced AML cells, creating an absolute gap in the expression of total amount of RUNX (RUNX1 + RUNX2 + RUNX3), which was confirmed by RT-qPCR (total amount of RUNX expressions were estimated by primers amplifying the specific sequence common to all RUNX family members). Luciferase reporter assay of GSTA2 promoter and chromatin immunoprecipitation (ChIP) assay in the proximal promoter region of GSTA2 gene proved the association of RUNX family members with this genomic region. These results indicated that total amount of RUNX family expressions modulate the expression of GSTA2 in AML cells, which might results in a paradoxical outbursts of RUNX1 moderately-inhibited AML cells. Since GSTA2 catabolizes and scavenges free radicals such as hydrogen peroxide (H2O2), and decreased intracellular free radicals promote acceleration of cell cycle progression, we next measured the intracellular accumulation of H2O2 in RUNX1 inhibited AML cells. As we have expected, intracellular amount of H2O2 was decreased in sh_Rx1_moderate-transduced AML cells and increased in AML cells transduced with sh_Rx1_profound. Additive transduction of sh_RNAs targeting GSTA2 to AML cells with sh_Rx1_moderate reverted the proliferation speed to the control level, underpinning that growth advantage of moderate RUNX1 inhibition could be attributed to the GSTA2 overexpressions. Taken together, these findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in anti-leukemia strategy. Disclosures No relevant conflicts of interest to declare.
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Tang, Chen-Yi, Mengrui Wu, Dongfeng Zhao, Diep Edwards, Abigail McVicar, Yuan Luo, Guochun Zhu i in. "Runx1 is a central regulator of osteogenesis for bone homeostasis by orchestrating BMP and WNT signaling pathways". PLOS Genetics 17, nr 1 (21.01.2021): e1009233. http://dx.doi.org/10.1371/journal.pgen.1009233.
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Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific (Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast−adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.
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Jiang, Qing, Xin Qin, Kenichi Nagano, Hisato Komori, Yuki Matsuo, Ichiro Taniuchi, Kosei Ito i Toshihisa Komori. "Different Requirements of CBFB and RUNX2 in Skeletal Development Among Calvaria, Limbs, Vertebrae and Ribs". International Journal of Molecular Sciences 23, nr 21 (31.10.2022): 13299. http://dx.doi.org/10.3390/ijms232113299.
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RUNX proteins, such as RUNX2, regulate the proliferation and differentiation of chondrocytes and osteoblasts. Haploinsufficiency of RUNX2 causes cleidocranial dysplasia, but a detailed analysis of Runx2+/– mice has not been reported. Furthermore, CBFB is required for the stability and DNA binding of RUNX family proteins. CBFB has two isoforms, and CBFB2 plays a major role in skeletal development. The calvaria, femurs, vertebrae and ribs in Cbfb2–/– mice were analyzed after birth, and compared with those in Runx2+/– mice. Calvarial development was impaired in Runx2+/– mice but mildly delayed in Cbfb2–/– mice. In femurs, the cortical bone but not trabecular bone was reduced in Cbfb2–/– mice, whereas both the trabecular and cortical bone were reduced in Runx2+/– mice. The trabecular bone in vertebrae increased in Cbfb2–/– mice but not in Runx2+/– mice. Rib development was impaired in Cbfb2–/– mice but not in Runx2+/– mice. These differences were likely caused by differences in the indispensability of CBFB and RUNX2, the balance of bone formation and resorption, or the number and maturation stage of osteoblasts. Thus, different amounts of CBFB and RUNX2 were required among the bone tissues for proper bone development and maintenance.
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Li, Weiping, Shujuan Xu, Shuang Lin i Wei Zhao. "Overexpression of Runt-Related Transcription Factor-2 Is Associated with Advanced Tumor Progression and Poor Prognosis in Epithelial Ovarian Cancer". Journal of Biomedicine and Biotechnology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/456534.
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Aim. To investigate clinical significance of runt-related transcription factor (RUNX)-2 in epithelial ovarian cancer (EOC).Methods. RUNX2 protein expression and its subcellular localization were detected by immunohistochemistry in 116 patients with EOC.Results. RUNX2 protein was predominantly expressed in cell nucleus of EOC tissues. The expression level of RUNX2 in EOC tissues was significantly higher than that in normal ovarian tissues(P<0.001). In addition, the nuclear labeling index (LI) of RUNX2 in tumor cells was significantly associated with the advanced clinical stage of EOC tissues(P=0.001). Moreover, EOC patients with high RUNX2 LI had significantly shorter overall(P<0.001)and progression-free(P=0.002)survival than those with low RUNX2 LI. Especially, subgroup analysis revealed that EOC patients with high clinical stages (III~IV) in high RUNX2 expression group demonstrated a significantly worse clinical outcome than those in low RUNX2 expression group, but patients with low clinical stages (I~II) had no significantly different prognosis between high and low RUNX2 expression groups.Conclusions. Our data suggest for the first time that RUNX2 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients. RUNX2 might be a novel prognostic marker of EOC.
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Nam, Seunghee, Yun-Hye Jin, Qing-Lin Li, Kwang-Youl Lee, Goo-Bo Jeong, Yoshiaki Ito, Junho Lee i Suk-Chul Bae. "Expression Pattern, Regulation, and Biological Role of Runt Domain Transcription Factor, run, in Caenorhabditis elegans". Molecular and Cellular Biology 22, nr 2 (15.01.2002): 547–54. http://dx.doi.org/10.1128/mcb.22.2.547-554.2002.
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ABSTRACT The Caenorhabditis elegans run gene encodes a Runt domain factor. Runx1, Runx2, and Runx3 are the three known mammalian homologs of run. Runx1, which plays an essential role in hematopoiesis, has been identified at the breakpoint of chromosome translocations that are responsible for human leukemia. Runx2 plays an essential role in osteogenesis, and inactivation of one allele of Runx2 is responsible for the human disease cleidocranial dysplasia. To understand the role of run in C. elegans, we used transgenic run::GFP reporter constructs and a double-stranded RNA-mediated interference method. The expression of run was detected as early as the bean stage exclusively in the nuclei of seam hypodermal cells and lasted until the L3 stage. At the larval stage, expression of run was additionally detected in intestinal cells. The regulatory elements responsible for the postembryonic hypodermal seam cells and intestinal cells were separately located within a 7.2-kb-long intron region. This is the first report demonstrating that an intron region is essential for stage-specific and cell type-specific expression of a C. elegans gene. RNA interference analysis targeting the run gene resulted in an early larva-lethal phenotype, with apparent malformation of the hypodermis and intestine. These results suggest that run is involved in the development of a functional hypodermis and gut in C. elegans. The highly conserved role of the Runt domain transcription factor in gut development during evolution from nematodes to mammals is discussed.
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Tang, Jun, Jing Xie, Wei Chen, Chenyi Tang, Jinjin Wu, Yiping Wang, Xue-Dong Zhou, Hou-De Zhou i Yi-Ping Li. "Runt-related transcription factor 1 is required for murine osteoblast differentiation and bone formation". Journal of Biological Chemistry 295, nr 33 (22.06.2020): 11669–81. http://dx.doi.org/10.1074/jbc.ra119.007896.
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Despite years of research investigating osteoblast differentiation, the mechanisms by which transcription factors regulate osteoblast maturation, bone formation, and bone homeostasis is still unclear. It has been reported that runt-related transcription factor 1 (Runx1) is expressed in osteoblast progenitors, pre-osteoblasts, and mature osteoblasts; yet, surprisingly, the exact function of RUNX1 in osteoblast maturation and bone formation remains unknown. Here, we generated and characterized a pre-osteoblast and differentiating chondrocyte-specific Runx1 conditional knockout mouse model to study RUNX1's function in bone formation. Runx1 ablation in osteoblast precursors and differentiating chondrocytes via osterix-Cre (Osx-Cre) resulted in an osteoporotic phenotype and decreased bone density in the long bones and skulls of Runx1f/fOsx-Cre mice compared with Runx1f/f and Osx-Cre mice. RUNX1 deficiency reduced the expression of SRY-box transcription factor 9 (SOX9), Indian hedgehog signaling molecule (IHH), Patched (PTC), and cyclin D1 in the growth plate, and also reduced the expression of osteocalcin (OCN), OSX, activating transcription factor 4 (ATF4), and RUNX2 in osteoblasts. ChIP assays and promoter activity mapping revealed that RUNX1 directly associates with the Runx2 gene promoter and up-regulates Runx2 expression. Furthermore, the ChIP data also showed that RUNX1 associates with the Ocn promoter. In conclusion, RUNX1 up-regulates the expression of Runx2 and multiple bone-specific genes, and plays an indispensable role in bone formation and homeostasis in both trabecular and cortical bone. We propose that stimulating Runx1 activity may be useful in therapeutic approaches for managing some bone diseases such as osteoporosis.
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Hass, Matthew R., Daniel Brissette, Sreeja Parameswaran, Mario Pujato, Omer Donmez, Leah C. Kottyan, Matthew T. Weirauch i Raphael Kopan. "Runx1 shapes the chromatin landscape via a cascade of direct and indirect targets". PLOS Genetics 17, nr 6 (10.06.2021): e1009574. http://dx.doi.org/10.1371/journal.pgen.1009574.
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Runt-related transcription factor 1 (Runx1) can act as both an activator and a repressor. Here we show that CRISPR-mediated deletion of Runx1 in mouse metanephric mesenchyme-derived mK4 cells results in large-scale genome-wide changes to chromatin accessibility and gene expression. Open chromatin regions near down-regulated loci enriched for Runx sites in mK4 cells lose chromatin accessibility in Runx1 knockout cells, despite remaining Runx2-bound. Unexpectedly, regions near upregulated genes are depleted of Runx sites and are instead enriched for Zeb transcription factor binding sites. Re-expressing Zeb2 in Runx1 knockout cells restores suppression, and CRISPR mediated deletion of Zeb1 and Zeb2 phenocopies the gained expression and chromatin accessibility changes seen in Runx1KO due in part to subsequent activation of factors like Grhl2. These data confirm that Runx1 activity is uniquely needed to maintain open chromatin at many loci, and demonstrate that Zeb proteins are required and sufficient to maintain Runx1-dependent genome-scale repression.
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Kimura, A., H. Inose, F. Yano, K. Fujita, T. Ikeda, S. Sato, M. Iwasaki i in. "Runx1 and Runx2 cooperate during sternal morphogenesis". Development 137, nr 7 (24.02.2010): 1159–67. http://dx.doi.org/10.1242/dev.045005.
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Inman, Claire K., Na Li i Paul Shore. "Oct-1 Counteracts Autoinhibition of Runx2 DNA Binding To Form a Novel Runx2/Oct-1 Complex on the Promoter of the Mammary Gland-Specific Gene β-casein". Molecular and Cellular Biology 25, nr 8 (15.04.2005): 3182–93. http://dx.doi.org/10.1128/mcb.25.8.3182-3193.2005.
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ABSTRACT The transcription factor Runx2 is essential for the expression of a number of bone-specific genes and is primarily considered a master regulator of bone development. Runx2 is also expressed in mammary epithelial cells, but its role in the mammary gland has not been established. Here we show that Runx2 forms a novel complex with the ubiquitous transcription factor Oct-1 to regulate the expression of the mammary gland-specific gene β-casein. The Runx2/Oct-1 complex forms on a Runx/octamer element which is highly conserved in casein promoters. Chromatin immunoprecipitation, RNA interference, promoter mutagenesis, and transient expression analyses were used to demonstrate that the Runx2/Oct-1 complex contributes to the transcriptional regulation of the β-casein gene. Analysis of the complex revealed autoinhibitory domains for DNA binding in both the N-terminal and the C-terminal regions of Runx2. Oct-1 stimulates the recruitment of Runx2 to the β-casein promoter by interacting with the C-terminal region of Runx2, suggesting that Oct-1 stimulates Runx2 recruitment by relieving the autoinhibition of Runx2 DNA binding. These findings demonstrate that Runx2 collaborates with Oct-1 and contributes to the expression of a mammary gland-specific gene.
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Fukushima-Nakase, Yoko, Yoshinori Naoe, Ichiro Taniuchi, Hajime Hosoi, Tohru Sugimoto i Tsukasa Okuda. "Shared and distinct roles mediated through C-terminal subdomains of acute myeloid leukemia/Runt-related transcription factor molecules in murine development". Blood 105, nr 11 (1.06.2005): 4298–307. http://dx.doi.org/10.1182/blood-2004-08-3372.
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Abstract AML1/Runx1 is a frequent target of human leukemia–associated gene aberration and encodes a transcription factor with nonredundant biologic functions in initial development of definitive hematopoiesis, T-cell development, and steady-state platelet production. AML1/Runx1 and 2 closely related family genes, AML2/Runx3 and AML3/Runx2/Cbfa1, present in mammals, comprise the Runt-domain transcription factor family. Although they have similar structural and biochemical properties, gene-targeting experiments have identified distinct biologic roles. To directly determine the presence of functional overlap among runt-related transcription factor (Runx) family molecules, we replaced the C-terminal portion of acute myeloid leukemia 1 (AML1) with that derived from its family members, which are variable in contrast to conserved Runt domain, using the gene knock-in method. We found that C-terminal portions of either AML2 or AML3 could functionally replace that of AML1 for myeloid development in culture and within the entire mouse. However, while AML2 substituted for AML1 could effectively rescue lymphoid lineages, AML3 could not, resulting in a smaller thymus and lymphoid deficiency in peripheral blood. Substitution by the C-terminal portion of AML3 also led to high infantile mortality and growth retardation, suggesting that AML1 has as yet unidentified effects on these phenotypes. Thus, the C-terminal portions of Runx family members have both similar and distinct biologic functions.
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Ozaki, Toshinori, Akira Nakagawara i Hiroki Nagase. "RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response". International Journal of Genomics 2013 (2013): 1–12. http://dx.doi.org/10.1155/2013/271347.
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A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.
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Liu, Jing, Eun-Sil Park, Thomas E. Curry i Misung Jo. "Periovulatory Expression of Hyaluronan and Proteoglycan Link Protein 1 (Hapln1) in the Rat Ovary: Hormonal Regulation and Potential Function". Endocrine Reviews 31, nr 2 (1.04.2010): 262–63. http://dx.doi.org/10.1210/edrv.31.2.9997.
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ABSTRACT Periovulatory follicular matrix plays an important role in cumulus-oocyte complex (COC) expansion, ovulation, and luteal formation. Hyaluronan and proteoglycan link protein 1 (HAPLN1), a component of follicular matrix, was shown to enhance COC expansion in vitro. However, the regulatory mechanisms of periovulatory expression of Hapln1 and its role in periovulatory granulosa cells have not been elucidated. We first determined the periovulatory expression pattern of Hapln1 using pregnant mare serum gonadotropin/human chorionic gonadotropin (hCG)-primed immature rat ovaries. Hapln1 expression was transiently induced both in intact ovaries and granulosa cells at 8 h and 12 h after hCG injection. This in vivo expression of Hapln1 was recapitulated by culturing preovulatory granulosa cells with hCG. The stimulatory effect of hCG was blocked by inhibition of protein kinase A, phosphatidylinositol dependent kinase, p38 MAPK, epidermal growth factor signaling, and prostaglandin synthesis, revealing key mediators involved in LH-induced Hapln1 expression. In addition, knockdown of Runx1 and Runx2 expression by small interfering RNA or inhibition of RUNX activities by dominant-negative RUNX decreased hCG or agonist-induced Hapln1 expression. Chromatin immunoprecipitation assays verified the in vivo binding of RUNX1 and RUNX2 to the Hapln1 promoter in periovulatory granulosa cells. Luciferase reporter assays revealed that mutation of the RUNX binding sites completely obliterated the agonist-induced activity of the Hapln1 promoter. These data conclusively identified RUNX proteins as the crucial transcription regulators for LH-induced Hapln1 expression. Functionally, treatment with HAPLN1 increased the viability of cultured granulosa cells and decreased the number of the cells undergoing apoptosis, whereas knockdown of Hapln1 expression decreased granulosa cells viability. This novel finding indicates that HAPLN1 may promote periovulatory granulosa cell survival, which would facilitate their differentiation into luteal cells.
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Martin, J. W., M. Zielenska, G. S. Stein, A. J. van Wijnen i J. A. Squire. "The Role of RUNX2 in Osteosarcoma Oncogenesis". Sarcoma 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/282745.
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Osteosarcoma is an aggressive but ill-understood cancer of bone that predominantly affects adolescents. Its rarity and biological heterogeneity have limited studies of its molecular basis. In recent years, an important role has emerged for the RUNX2 “platform protein” in osteosarcoma oncogenesis. RUNX proteins are DNA-binding transcription factors that regulate the expression of multiple genes involved in cellular differentiation and cell-cycle progression. RUNX2 is genetically essential for developing bone and osteoblast maturation. Studies of osteosarcoma tumours have revealed that the RUNX2 DNA copy number together with RNA and protein levels are highly elevated in osteosarcoma tumors. The protein is also important for metastatic bone disease of prostate and breast cancers, while RUNX2 may have both tumor suppressive and oncogenic roles in bone morphogenesis. This paper provides a synopsis of the current understanding of the functions of RUNX2 and its potential role in osteosarcoma and suggests directions for future study.
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Goyama, Susumu, Yuko Yamaguchi, Yoichi Imai, Masahito Kawazu, Masahiro Nakagawa, Takashi Asai, Keiki Kumano i in. "The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region". Blood 104, nr 12 (1.12.2004): 3558–64. http://dx.doi.org/10.1182/blood-2004-04-1535.
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Acute myelogenous leukemia 1 (AML1; runt-related transcription factor 1 [Runx1]) is a member of Runx transcription factors and is essential for definitive hematopoiesis. Although AML1 possesses several subdomains of defined biochemical functions, the physiologic relevance of each subdomain to hematopoietic development has been poorly understood. Recently, the consequence of carboxy-terminal truncation in AML1 was analyzed by the hematopoietic rescue assay of AML1-deficient mouse embryonic stem cells using the gene knock-in approach. Nonetheless, a role for specific internal domains, as well as for mutations found in a human disease, of AML1 remains to be elucidated. In this study, we established an experimental system to efficiently evaluate the hematopoietic potential of AML1 using a coculture system of the murine embryonic para-aortic splanchnopleural (P-Sp) region with a stromal cell line, OP9. In this system, the hematopoietic defect of AML1-deficient P-Sp can be rescued by expressing AML1 with retroviral infection. By analysis of AML1 mutants, we demonstrated that the hematopoietic potential of AML1 was closely related to its transcriptional activity. Furthermore, we showed that other Runx transcription factors, Runx2/AML3 or Runx3/AML2, could rescue the hematopoietic defect of AML1-deficient P-Sp. Thus, this experimental system will become a valuable tool to analyze the physiologic function and domain contribution of Runx proteins in hematopoiesis.
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Goyama, Susumu, Janet Schibler, Yalan Rao, Mark Wunderlich, Kevin A. Link, Gang Huang i James C. Mulloy. "Pro-Survival Role of RUNX1 in Acute Myeloid Leukemia with Common Fusion Proteins". Blood 118, nr 21 (18.11.2011): 870. http://dx.doi.org/10.1182/blood.v118.21.870.870.
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Abstract Abstract 870 RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Blocking RUNX1 function has been implicated in development of core-binding factor (CBF) leukemia and MLL-rearranged leukemia. In addition, inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in CBF- and MLL-rearranged leukemias, raising the possibility that a certain level of RUNX1 activity is required for efficient propagation of these leukemia cells. To determine the precise role of RUNX1 in specific types of myeloid neoplasms, we assessed RUNX1 functions in primary human CD34+ cord blood cells and those transduced with CBF related fusion oncoproteins [AML1-ETO (AE) or CBFB-MYH11 (CM)] or a MLL fusion oncoprotein, MLL-AF9 (MA9). RUNX1 was abundantly expressed and phosphorylated in AE-, CM-, and MA9-expressing long-term cultured cells. RUNX1 overexpression induced myeloid differentiation in normal CD34+ cells and prevented their long-term proliferation. Leukemogenic RUNX1 mutants lost the ability to induce differentiation, and a C-terminal truncated RUNX1 mutant conferred long-term (over 3 months) proliferative ability to CD34+ cells. RUNX1 overexpression also induced differentiation in CBF leukemia cells (AE- or CM-expressing cells). Interestingly, block of proper RUNX1 function, either by shRNA driven knockdown or forced expression of dominant-negative type mutants, showed growth inhibitory effects on CBF leukemia cells, suggesting that a certain level of RUNX1 activity is required for CBF leukemogenesis. Strikingly, block of RUNX1 function, but not RUNX1 overexpression, resulted in substantial growth inhibition of MA9 cells through enhanced apoptosis and cell cycle arrest. A xenotransplantation assay further demonstrated that RUNX1 knockdown inhibited human AML development by MA9 in vivo. The growth inhibitory effect of shRNA-mediated RUNX1 knockdown on MA9 cells was rescued by reintroduction of RUNX1, and partially restored by another RUNX transcription factor RUNX2. Thus, RUNX proteins have a growth-promoting role during MA9-driven leukemogenesis. These results contrast with those obtained using a mouse transplantation model that showed loss of Runx1 accelerates the development of MLL-ENL driven leukemia. The cause of this discrepancy is unclear, but it could be explained by species differences (human vs mouse), different experimental assays (homologous transplantation vs xenotransplantation), or the compensatory mechanism of Runx1 deletion with other Runx proteins (Runx2 and Runx3) in Runx1 knockout mice. Further studies will be needed to determine the precise roles of RUNX1 in human MLL leukemias. Finally, we assessed molecular changes in RUNX1-depleted MA9 cells and found CDKN1A upregulation and BCL2 downregulation. We also confirmed that CDKN1A depletion and BCL2 overexpression have growth-promoting effects on MA9 cells. Therefore, it appears that these molecular changes contribute to the attenuated growth of RUNX1-depleted MA9 cells. However, MA9 cells with CDKN1A depletion or BCL2 overexpression were not fully rescued from the effects of RUNX1 depletion, indicating the importance of other RUNX1 targets to support cell survival and proliferation. In conclusion, our human cell system confirmed a tumor suppressor role of RUNX1 in normal CD34+ cells, and unveiled an unexpected growth-promoting role of RUNX1 in MLL-rearranged human leukemia cells. In CBF leukemia cells, precise control of RUNX1 level appears to be important for optimal cell growth (Fig.1). Taken together, these findings suggest that partial reduction of RUNX1 activity expands myeloid progenitors by blocking differentiation, while further reduction of RUNX1 results in cell cycle arrest and increased cell death in human cells. Therefore, inhibiting RUNX1 activity rather than enhancing it will be a promising therapeutic strategy for certain types of leukemia, particularly for leukemias with common fusion proteins. Disclosures: No relevant conflicts of interest to declare.
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Kimura, A., F. Yano, H. Inose, K. Fujita, H. Kawaguchi, U. Chung, K. Shinomiya i S. Takeda. "Cooperative induction of chondrocyte differentiation by Runx1 and Runx2". Bone 44 (maj 2009): S150. http://dx.doi.org/10.1016/j.bone.2009.01.329.
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Yoshida, C. A. "Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog". Genes & Development 18, nr 8 (15.04.2004): 952–63. http://dx.doi.org/10.1101/gad.1174704.
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Ukkat, Jörg, Cuong Hoang-Vu, Bogusz Trojanowicz i Artur Rebelo. "Osteocalcin, Osteopontin and RUNX2 Expression in Patients’ Leucocytes with Arteriosclerosis". Diseases 9, nr 1 (12.03.2021): 19. http://dx.doi.org/10.3390/diseases9010019.
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Introduction: Calcification is a highly relevant process in terms of development of cardiovascular diseases, and its prevention may be the key to prevent disease progression in patients. In this study we investigated the expression of osteocalcin (OC), osteopontin (OPN) and RUNX2 in patients’ leukocytes and their possible role as diagnostic markers for cardiovascular diseases. Materials and Methods: Leucocytes from 38 patients were collected in the Department of Surgery of Martin-Luther-University Halle, including 8 patients without arteriosclerotic disease (PAD−) and 30 patients with symptomatic arteriosclerotic disease (PAD+). Patients’ leucocytes, in vitro calcified human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (VSMC) were subjected to qPCR analyses with TaqMan probes, which are specific for OC, OPN and RUNX2. Additionally, the interaction between monocytes and calcified HUVEC and VSMC was investigated in adhesion assays. Results: The leucocytes obtained from patients with symptomatic arteriosclerotic disease (PAD+) demonstrated decreased mRNA level expression of Osteocalcin, while OPN and RUNX2 were significantly upregulated in comparison to asymptomatic patients. The induction of calcification in HUVEC and VSMC cells led to an increased expression of OC, OPN and RUNX2. Immunocytochemistry of calcified HUVEC and VSMC revealed stronger expression of OC, OPN and RUNX2 in calcified cells. Conclusion: To conclude, these data demonstrate that symptomatic arteriosclerotic disease has a correlation with OC, OPN and RUNX2. The biological rationale of OC, OPN and RUNX-2 remains not yet entirely understood for atherosclerotic disease, which means it needs further investigation.
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Greives, Matthew R., Eric A. Odessey, Darrel J. Waggoner, Deana S. Shenaq, Swaroop Aradhya, Allison Mitchell, Emma Whitcomb, Neil Warshawsky, Tong-Chuan He i Russell R. Reid. "RUNX2 Quadruplication". Journal of Craniofacial Surgery 24, nr 1 (styczeń 2013): 126–29. http://dx.doi.org/10.1097/scs.0b013e31826686d3.
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Ehrhardt, Götz R. A., Atsushi Hijikata, Hiroshi Kitamura, Osamu Ohara, Ji-Yang Wang i Max D. Cooper. "Discriminating gene expression profiles of memory B cell subpopulations". Journal of Experimental Medicine 205, nr 8 (14.07.2008): 1807–17. http://dx.doi.org/10.1084/jem.20072682.
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Morphologically and functionally distinct subpopulations of human memory B (BMem) cells are identifiable by either their expression of CD27 or Fc receptor–like 4 (FCRL4), an immunoglobulin domain containing a receptor with strong inhibitory potential. We have conducted comparative transcriptome and proteome analyses of FCRL4+ and FCRL4− BMem cells and found that these two subsets have very distinctive expression profiles for genes encoding transcription factors, cell-surface proteins, intracellular signaling molecules, and modifiers of the cell-cycle status. Among the differentially expressed transcription factors, runt-related transcription factor 1 (RUNX1) transcript levels were up-regulated in FCRL4− cells, whereas RUNX2 transcripts were preferentially detected in FCRL4+ cells. In vitro evidence for FCRL4 promoter responsiveness and in vivo promoter occupancy suggested that RUNX transcription factors are involved in the generation of these BMem cell subpopulations. A distinctive signature profile was defined for the FCRL4+ BMem cells by their expression of CD11c, receptor activator for nuclear factor κB ligand, and FAS cell-surface proteins, in combination with increased levels of SOX5, RUNX2, DLL1, and AICDA expression. We conclude that this recently identified subpopulation of BMem cells, which normally resides in epithelial tissue-based niches, may serve a unique role in mucosal defense and, conversely, as a target for neoplastic transformation events.
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Stewart, Monica, Nancy MacKay, Ewan R. Cameron i James C. Neil. "The Common Retroviral Insertion Locus Dsi1 Maps 30 Kilobases Upstream of the P1 Promoter of the Murine Runx3/Cbfa3/Aml2 Gene". Journal of Virology 76, nr 9 (1.05.2002): 4364–69. http://dx.doi.org/10.1128/jvi.76.9.4364-4369.2002.
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ABSTRACT The Dsi1 locus was identified as a common integration site for Moloney murine leukemia virus (MLV) in rat thymic lymphomas, but previous efforts to identify a gene affected by these insertions were unsuccessful. We considered the Runx3 gene a potential candidate on the basis of genetic mapping which showed that Dsi1 and Runx3 are closely linked on mouse chromosome 4 and the precedent of the related Runx2 gene, which emerged recently as a Myc-collaborating gene activated by retroviral insertion in thymic lymphomas of CD2-MYC mice. We now report the physical mapping of the Dsi1 locus to a site 30 kb upstream of the distal (P1) promoter of the murine Runx3 gene. Comparison with the syntenic region of human chromosome 1 shows that the next gene is over 250 kb 5′ to Runx3, suggesting that Runx3 may be the primary target of retroviral insertions at Dsi1. Screening of CD2-MYC lymphomas for rearrangements at Dsi1 revealed a tumor cell line harboring an MLV provirus at this locus, in the orientation opposite that of Runx3. Proviral insertion was associated with very high levels of expression of Runx3, with a preponderance of transcripts arising at the P1 promoter. These results confirm that Runx3 is a target of retroviral insertions at Dsi1 and indicate that Runx3 can act as an alternative to Runx2 as a Myc-collaborating gene in thymic lymphoma.
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Talebian, Laleh, Zhe Li, Torrey L. Gallagher, Yalin Guo, Caroline L. Speck, Terryl Stacy i Nancy A. Speck. "A Hypomorphic Cbfb Allele Reveals Requirements for the Development of T Lymphocytes, Granulocytes, and Monocytes/Macrophages, and for Maintaining Proper Numbers of Hematopoietic Progenitors." Blood 104, nr 11 (16.11.2004): 1596. http://dx.doi.org/10.1182/blood.v104.11.1596.1596.
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Abstract CBFβ is the non-DNA binding subunit of the core binding factors, and is required for both the functions of Runx1 in hematopoiesis and Runx2 in osteogenesis. Homozygous disruption of Cbfb results in embryonic lethality at mid-gestation and a severe impairment of fetal liver hematopoiesis, a phenotype similar to Runx1 deficiency. To examine Cbfb requirements at later stages of hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). Mice homozygous for the Cbfbrss allele have a 4- to 5-fold reduction in CBFβ protein levels, while Cbfbrss/− mice have an 8- to 10-fold reduction in CBFβ concentration. Cbfbrss/rss and Cbfbrss/− mice die at P0 for unknown reasons and display minor defects in bone ossification. Granulocyte and macrophage differentiation at E17.5 is impaired in both Cbfbrss/rss and Cbfbrss/−animals, as evidenced by a 2- to 3- fold decrease in GR1+ and Mac1+ cells. The percentages of Ter119+, B220+, and CD19+ cells are normal. Fetal liver hematopoietic progenitor numbers, as determined by cell surface marker and functional analyses, are increased approximately 2-fold. The most severe defects are in the T cell lineage. Cbfbrss/rss fetuses have reduced thymus cellularity and lower numbers of CD8 SP T cells, consistent with a role for Runx1 and Runx3 in epigenetic CD4 silencing. A further 2-fold reduction in CBFβ levels in Cbfbrss/− fetuses results in an absence of CD4/8 SP and DP cells. These hematopoietic defects were also seen upon transplantation of Cbfbrss/rss and Cbfbrss/− fetal liver cells into congenic Ly5.1/5.2 mice. Our data indicate that the threshold level of CBFβ required for normal hematopoiesis, bone development, and postnatal viability is somewhere between 25%-50% of its normal concentration. The data demonstrate that T cell development is particularly sensitive to CBFβ levels, and both granulocyte and macrophage differentiation require CBFβ. Since the conditional knockout of Runx1 in the adult mouse reported by Ichikawa et al. (Nat Med.10, 299, 2004) did not cause either granulocyte or monocyte/macrophage defects, we hypothesize that Runx2 and/or Runx3 are also required in these lineages. Hemizygosity for CBFB-MYH11, the product of the inv(16), is associated with a more severe phenotype than is seen in the Cbfb rss/− fetuses (Castilla et al. Cell87, 687, 1996). We therefore conclude that the hematopoietic consequences for cells expressing the inv(16) are equivalent to a greater than 10-fold reduction in the level of functional CBFβ.
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Kanto, Satoru, Marcin Grynberg, Yoshiyuki Kaneko, Jun Fujita i Masanobu Satake. "A variant of Runx2 that differs from the bone isoform in its splicing is expressed in spermatogenic cells". PeerJ 4 (4.04.2016): e1862. http://dx.doi.org/10.7717/peerj.1862.
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Background.Members of theRunxgene family encode transcription factors that bind to DNA in a sequence-specific manner. Among the three Runx proteins, Runx2 comprises 607 amino acid (aa) residues, is expressed in bone, and plays crucial roles in osteoblast differentiation and bone development. We examined whether theRunx2gene is also expressed in testes.Methods.Murine testes from 1-, 2-, 3-, 4-, and 10-week-old male mice of the C57BL/6J strain andW∕Wvstrain were used throughout the study. Northern Blot Analyses were performed using extracts form the murine testes. Sequencing of cDNA clones and 5′-rapid amplification of cDNA ends were performed to determine the full length of the transcripts, which revealed that the testicular Runx2 comprises 106 aa residues coding novel protein. Generating an antiserum using the amino-terminal 15 aa of Runx2 (Met1to Gly15) as an antigen, immunoblot analyses were performed to detect the predicted polypeptide of 106 aa residues with the initiating Met1. With the affinity-purified anti-Runx2 antibody, immunohistochemical analyses were performed to elucidate the localization of the protein. Furthermore, bioinformatic analyses were performed to predict the function of the protein.Results.ARunx2transcript was detected in testes and was specifically expressed in germ cells. Determination of the transcript structure indicated that the testicularRunx2is a splice isoform. The predicted testicular Runx2 polypeptide is composed of only 106 aa residues, lacks a Runt domain, and appears to be a basic protein with a predominantly alpha-helical conformation. Immunoblot analyses with an anti-Runx2 antibody revealed that Met1in the deduced open reading frame ofRunx2is used as the initiation codon to express an 11 kDa protein. Furthermore, immunohistochemical analyses revealed that the Runx2 polypeptide was located in the nuclei, and was detected in spermatocytes at the stages of late pachytene, diplotene and second meiotic cells as well as in round spermatids. Bioinformatic analyses suggested that the testicular Runx2 is a histone-like protein.Discussion.A variant ofRunx2that differs from the bone isoform in its splicing is expressed in pachytene spermatocytes and round spermatids in testes, and encodes a histone-like, nuclear protein of 106 aa residues. Considering its nuclear localization and differentiation stage-dependent expression, Runx2 may function as a chromatin-remodeling factor during spermatogenesis. We thus conclude that a singleRunx2gene can encode two different types of nuclear proteins, a previously defined transcription factor in bone and cartilage and a short testicular variant that lacks a Runt domain.
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Matheny, Christina J., Takeshi Corpora, Maren E. Speck, Ting-Lei Gu, John H. Bushweller i Nancy A. Speck. "Biochemical and In Vivo Characterization of Amino Acid Substitutions in the Runx1 (AML1) Runt Domain Found in FPD/AML, AML M0, and Cleidocranial Dysplasia (CCD) Patients." Blood 104, nr 11 (16.11.2004): 464. http://dx.doi.org/10.1182/blood.v104.11.464.464.
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Abstract Runx1 and CBF β are the DNA-binding and non DNA-binding subunits of a core-binding factor that is required for hematopoiesis, and that is frequently mutated in leukemia. Runx2 is the DNA-binding subunit of a core-binding factor required for bone formation. Mono-allelic deletion, nonsense, frameshift, and missense mutations have been found in RUNX1 in familial platelet disorder with predisposition for acute myelogenous leukemia (FPD/AML) and in myelodysplastic syndrome (MDS), and biallelic mutations in RUNX1 are found in 20% of AML M0 patients. Similar types of mono-allelic mutations have been found in RUNX2 in patients with cleidocranial dysplasia (CCD), an inherited skeletal syndrome. FPD/AML and CCD pedigrees have revealed varying degrees of disease severity depending on the nature of the specific mutation. Additionally, it has been observed that mutations involving amino acids in the DNA binding Runt domain that directly contact DNA are associated primarily with Runx1 and hematopoietic disorders, while mutations predicted to disrupt CBF β binding or the Runt domain structure are found only in Runx2 in CCD patients. We introduced 21 amino acid substitutions into the Runt domain of Runx1 identified in FPD/AML, AML M0, and CCD patients, and quantified their effects on DNA binding, heterodimerization with CBFβ, and the Runt domain structure using yeast one- and two-hybrid, quantitative electrophoretic mobility shift, heteronuclear single quantum correlation spectroscopy, and urea denaturation experiments. To address the impact on in vivo function, several of these point mutations were engineered into the endogenous Runx1 allele in mice. These five mutations include: R177X, R174Q, T149A, T161A, and L148F. R177X is found in FPD/AML patients and truncates Runx1 two amino acids before the C-terminal boundary of the Runt domain. R174Q (found in FPD/AML and CCD) disrupts DNA binding 1000-fold, but does not disrupt CBFb binding or perturb the Runt domain fold. T149A (found only in CCD) disrupts CBFβ binding 13-fold while T161A (not found in patients) disrupts CBFβ binding 40-fold. Both T149A and T161A slightly perturb the Runt domain fold, but do not alter DNA binding affinity. L148F (found in CCD) also disrupts the Runt domain fold, and decreases DNA binding. All animals heterozygous for these alleles are viable. Mice homozygous for R177X and R174Q die during gestation. Mice homozygous for the T149A and T161A mutations, on the other hand, are born at normal Mendelian frequencies, but 62% and 100%, respectively, die by or at three weeks of age from an undetermined cause. The effects of these mutations on hematopoietic progenitor and platelet numbers, both of which are affected in FPD/AML patients, will be presented. We conclude that mutations that affect CBFβ binding result in hypomorphic Runx1 alleles, while mutations involving DNA contacts result in more severe inactivation of Runx1 function. Thus FPD/AML, AML M0, and MDS require mutations that severely inactivate Runx1 function, while CCD can result from more subtle alterations in Runx2.
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van der Deen, Margaretha, Hanna Taipaleenmäki, Ying Zhang, Nadiya M. Teplyuk, Anurag Gupta, Senthilkumar Cinghu, Kristen Shogren i in. "MicroRNA-34c Inversely Couples the Biological Functions of the Runt-related Transcription Factor RUNX2 and the Tumor Suppressor p53 in Osteosarcoma". Journal of Biological Chemistry 288, nr 29 (29.05.2013): 21307–19. http://dx.doi.org/10.1074/jbc.m112.445890.
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Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3′-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.
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Kuo, Ya-Huei, Susan Heilman, Amy Chen, Pu P. Liu, Rachel Gernstein, Scott Kogan i Lucio H. Castilla. "Cbfb-MYH11 Induces Expansion of a Lin-Kit+Sca1- Abnormal Progenitor Compartment that Predisposes Acute Myeloid Leukemia in Mice." Blood 104, nr 11 (16.11.2004): 543. http://dx.doi.org/10.1182/blood.v104.11.543.543.
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Abstract Acute myeloid leukemia (AML) samples with chromosome 16 inversion express the CBFb-MYH11 fusion gene. One of three RUNX genes (RUNX1, RUNX2, and RUNX3) encode the α-subunit and CBFb encodes the β subunit of the heterodimeric transcription factor CBF. This transcription factor is a key regulator of multiple steps on hematopoietic differentiation. Studies in the mouse have determined that Cbfb-MYH11 expression impairs hematopoiesis, and that it induces AML in collaboration with other mutations. To further study the effects of Cbfb-MYH11 expression in hematopoiesis and leukemogenesis, we created a Cbfb-MYH11 conditional knock-in model (Cbfb56M), using the Cre-loxP recombination system. In this model, the floxed Cbfb allele expresses wildtype Cbfb, and the downstream Cbfb-MYH11 is induced upon Cre-mediated deletion. Floxed heterozygous and homozygous Cbfbfb56M mice are disease-free, indicating that Cbfb expressed from the floxed allele is functional. In addition, Cbfb-MYH11 was efficiently induced in over 80% of bone marrow cells from Cbfb56M/+/Mx1-Cre mice after pIpC injection. The preleukemic effects of Cbfb-MYH11 in hematopoiesis were analyzed using induced mice and non-competitive repopulation assays. First, circulating B-cells were reduced soon after Cbfb-MYH11 induction, and a significant differentiation block at the pre-pro B-cell stage was detected in the bone marrow. Second, thymic T-cell differentiation of induced mice showed impairment of DN2 to DN3 stage and reduction of thymic size in 3/10 induced mice analyzed. Interestingly, the number of circulating T cells was unaffected in repopulation assays. Third, platelets were reduced 50% in peripheral blood and megakaryocyte number was reduced in bone marrow. Fourth, we found an expanded abnormal progenitor compartment (Lin-kit+Sca1-) that accumulated in the bone marrow and spleen. In vitro differentiation assays showed a 2-to-3 fold increase of Cbfb-MYH11 colonies when compared to controls. The colony size was smaller, and showing partial differentiation deficiency. Interestingly, the colony numbers declined upon serial plating below controls. Taken together these results indicate that Cbfb-MYH11 induce accumulation of late progenitors (primarily myeloid progenitors) with limited self-renewal potential. Acute myeloid leukemia arised spontaneously 4 to 6 months after Cbfb-MYH11 induction, with expansion of blast- and monoblastic-like leukemic cells defined as Lin-kit+Sca1-. Leukemic mice showed infiltration in several tissues, including spleen, liver, brain, and lungs. To test whether a second “hit” is necessary in this model, we used bone marrow transduction assays to co-express Cbfb-MYH11 and the candidate cooperating gene Runx2. Recipient mice developed AML with similar phenotype 6 to 12 weeks post transplantation, while control mice remained healthy for 6 months. This study demonstrates that Cbfb-MYH11 expression (i) defines a preleukemic stage with hematopoietic differentiation block at stages associated with Runx function, (ii) the accumulation of an abnormal progenitor cell population (Lin-/kit+/Sca1-), (iii) induces additional mutations to efficiently develop AML, and (iv) synergizes with Runx2 in AML development.
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Hesse, Eric, Hiroaki Saito, Riku Kiviranta, Diego Correa, Kei Yamana, Lynn Neff, Daniel Toben i in. "Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity". Journal of Cell Biology 191, nr 7 (20.12.2010): 1271–83. http://dx.doi.org/10.1083/jcb.201009107.
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Runx2 is indispensable for osteoblast lineage commitment and early differentiation but also blocks osteoblast maturation, thereby causing bone loss in Runx2 transgenic mice. Zinc finger protein 521 (Zfp521) antagonizes Runx2 in vivo. Eliminating one Zfp521 allele mitigates the cleidocranial dysplasia–like phenotype of newborn Runx2+/− mice, whereas overexpressing Zfp521 exacerbates it. Overexpressing Zfp521 also reverses the severe osteopenia of adult Runx2 transgenic mice. Zfp521 binds to both Runx2 and histone deacetylase 3 (HDAC3), promotes their association, and antagonizes Runx2 transcriptional activity in an HDAC3-dependent manner. Mutating the Zfp521 zinc finger domains 6 and 26 reduces the binding of Zfp521 to Runx2 and inhibition of Runx2 activity. These data provide evidence that Zfp521 antagonizes Runx2 in vivo and thereby regulates two stages of osteoblast development, early during mesenchymal cell lineage commitment and later during osteoblast maturation. Thus, the balance and molecular interplay between Zfp521 and Runx2 contribute to the control of osteoblast differentiation, skeletal development, and bone homeostasis.
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Bushweller, John H., Stephen M. Lukasik i Nancy A. Speck. "The CBFb-SMMHC Oncoprotein Inhibits Binding of the Runx1 Runt Domain to DNA." Blood 106, nr 11 (16.11.2005): 2709. http://dx.doi.org/10.1182/blood.v106.11.2709.2709.
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Abstract Core-binding factors (CBFs) are heterodimeric transcriptional factors consisting of a DNA-binding Runx1 (CBFα) subunit and a CBFβ subunit. Cbfβ allosterically increases the affinity of Runx1 for DNA ~2.5 fold. CBF subunits are encoded by four genes in mammals. RUNX1 (AML1), RUNX2, and RUNX3 encode for CBFα subunits, and CBFB encodes the CBFβ subunit. Homozygous disruption of either the Runx1 or the Cbfb genes in mice results in essentially identical phenotypes: midgestation embryonic lethality accompanied by extensive hemorrhaging and a profound block at the fetal liver stage of hematopoiesis. In humans, chromosomal rearrangements that disrupt the Runx1 and CBFB genes are associated with a significant percentage of leukemias. CBFβ is disrupted in acute myeloid leukemia by inv(16)(p13;q22), t(16;16), and del(16)(q22). These translocations result in the production of novel fusion proteins containing most of the CBFβ protein fused to the C-terminal coiled-coil domain from smooth muscle myosin heavy chain (SMMHC) encoded by the MYH11 gene. A knock-in of the CBFB-MYH11 allele in mice resulted in embryonic lethality with a profound block in hematopoietic development, the same phenotype observed for the Runx1 and Cbfb knockouts. We recently demonstrated that the CBFβ-SMMHC fusion protein binds to the DNA binding Runt domain from Runx1 with both higher affinity and altered stoichiometry relative to native CBFβ. We also provided NMR-based evidence for multiple sites of contact between Runx1 and CBFβ-SMMHC, proving the role of the SMMHC sequence in creating this altered affinity. Here we demonstrate that CBFβ-SMMHC inhibits DNA binding of the Runx1 Runt domain by ~6-fold for the CD4 dual-site silencer element. Cross-saturation NMR mapping on the Runt domain in complex with CBFβ-SMMHC reveals that the SMMHC portion of the oncoprotein makes contacts with β-strands 1 and 2 in the Runt domain. We propose that the inhibition of DNA-binding and increased affinity combine to mediate the dysregulation of Runx-regulated genes caused by CBFβ-SMMHC. These results also clearly suggest that targeting of the CBFβ-SMMHC protein for drug development may well be a viable approach for the treatment of the associated leukemia.
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Takarada, Takeshi. "Recent advances in Runx2 research". Folia Pharmacologica Japonica 144, nr 2 (2014): 98. http://dx.doi.org/10.1254/fpj.144.98.
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Jeong, Jae-Hwan, Youn-Kwan Jung, Hyo-Jin Kim, Jung-Sook Jin, Hyun-Nam Kim, Sang-Min Kang, Shin-Yoon Kim i in. "The Gene for Aromatase, a Rate-Limiting Enzyme for Local Estrogen Biosynthesis, Is a Downstream Target Gene of Runx2 in Skeletal Tissues". Molecular and Cellular Biology 30, nr 10 (15.03.2010): 2365–75. http://dx.doi.org/10.1128/mcb.00672-09.
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ABSTRACT The essential osteoblast-related transcription factor Runx2 and the female steroid hormone estrogen are known to play pivotal roles in bone homeostasis; however, the functional interaction between Runx2- and estrogen-mediated signaling in skeletal tissues is minimally understood. Here we provide evidence that aromatase (CYP19), a rate-limiting enzyme responsible for estrogen biosynthesis in mammals, is transcriptionally regulated by Runx2. Consistent with the presence of multiple Runx2 binding sites, the binding of Runx2 to the aromatase promoter was demonstrated in vitro and confirmed in vivo by chromatin immunoprecipitation assays. The bone-specific aromatase promoter is activated by Runx2, and endogenous aromatase gene expression is upregulated by Runx2 overexpression, establishing the aromatase gene as a target of Runx2. The biological significance of the Runx2 transcriptional control of the aromatase gene is reflected by the enhanced estrogen biosynthesis in response to Runx2 in cultured cells. Reduced in vivo expression of skeletal aromatase gene and low bone mineral density are evident in Runx2 mutant mice. Collectively, these findings uncover a novel link between Runx2-mediated osteoblastogenic processes and the osteoblast-mediated biosynthesis of estrogen as an osteoprotective steroid hormone.
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Li, Na, Dongwei Luo, Xiaoxia Hu, Wei Luo, Guanghua Lei, Qian Wang, Ting Zhu, Junxia Gu, Yaojuan Lu i Qiping Zheng. "RUNX2 and Osteosarcoma". Anti-Cancer Agents in Medicinal Chemistry 15, nr 7 (13.07.2015): 881–87. http://dx.doi.org/10.2174/1871520615666150304151228.
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Fujita, Takashi, Yasutaka Azuma, Ryo Fukuyama, Yuji Hattori, Carolina Yoshida, Masao Koida, Kiyokazu Ogita i Toshihisa Komori. "Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling". Journal of Cell Biology 166, nr 1 (28.06.2004): 85–95. http://dx.doi.org/10.1083/jcb.200401138.
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Runx2 and phosphatidylinositol 3-kinase (PI3K)–Akt signaling play important roles in osteoblast and chondrocyte differentiation. We investigated the relationship between Runx2 and PI3K-Akt signaling. Forced expression of Runx2 enhanced osteoblastic differentiation of C3H10T1/2 and MC3T3-E1 cells and enhanced chondrogenic differentiation of ATDC5 cells, whereas these effects were blocked by treatment with IGF-I antibody or LY294002 or adenoviral introduction of dominant-negative (dn)–Akt. Forced expression of Runx2 or dn-Runx2 enhanced or inhibited cell migration, respectively, whereas the enhancement by Runx2 was abolished by treatment with LY294002 or adenoviral introduction of dn-Akt. Runx2 up-regulated PI3K subunits (p85 and p110β) and Akt, and their expression patterns were similar to that of Runx2 in growth plates. Treatment with LY294002 or introduction of dn-Akt severely diminished DNA binding of Runx2 and Runx2-dependent transcription, whereas forced expression of myrAkt enhanced them. These findings demonstrate that Runx2 and PI3K-Akt signaling are mutually dependent on each other in the regulation of osteoblast and chondrocyte differentiation and their migration.
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Shi, Xiuming, Vishwa Deepak, Linghui Wang, Xueqing Ba, Toshihisa Komori, Xianlu Zeng i Wenguang Liu. "Thrombospondin-1 Is a Putative Target Gene of Runx2 and Runx3". International Journal of Molecular Sciences 14, nr 7 (10.07.2013): 14321–32. http://dx.doi.org/10.3390/ijms140714321.
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Zhang, He-Yu, Long Jin, Gail A. Stilling, Katharina H. Ruebel, Kendra Coonse, Yoshinori Tanizaki, Avraham Raz i Ricardo V. Lloyd. "RUNX1 and RUNX2 upregulate Galectin-3 expression in human pituitary tumors". Endocrine 35, nr 1 (20.11.2008): 101–11. http://dx.doi.org/10.1007/s12020-008-9129-z.
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Salingcarnboriboon, Ruchanee, Kunikazu Tsuji, Toshihisa Komori, Kazuhisa Nakashima, Yoichi Ezura i Masaki Noda. "Runx2 Is a Target of Mechanical Unloading to Alter Osteoblastic Activity and Bone Formation in Vivo". Endocrinology 147, nr 5 (1.05.2006): 2296–305. http://dx.doi.org/10.1210/en.2005-1020.
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Molecular mechanisms underlying unloading-induced reduction of bone formation have not yet been fully understood. In vitro, Runx2 has been suggested to be involved in mechanical signaling in osteoblasts. However, the roles of Runx2 in vivo during the bone response to mechanical stimuli have not yet been known. The purpose of this paper was to examine the roles of Runx2 in unloading-induced bone loss in vivo. Tail suspension was conducted for 2 wk using 9- to 11-wk-old Runx2 heterozygous knockout mice (Runx2+/−) and wild-type (Wt) littermates. Bones were subjected to two-dimensional micro-x-ray computed tomography, bone histomorphometry and RT-PCR analyses. Loss of half Runx2 gene dosage-exacerbated unloading-induced bone loss in trabecular and cortical envelopes. Unloading-induced reduction in mineral apposition rate and bone formation rate in cortical bone as well as trabecular bone was exacerbated in Runx2+/− mice, compared with Wt mice. Bone resorption parameters were not significantly affected by unloading or Runx2+/− genotype. Basal Runx2 and osterix mRNA levels in bone were reduced by 50% in Wt, whereas unloading in Runx2+/− mice did not further alter Runx2 and osterix mRNA levels. In contrast, osteocalcin mRNA levels were reduced by unloading, regardless of Runx2 gene dosage. These data demonstrated that full Runx2 gene dosage is required for maintaining normal function of osteoblasts in mechanical unloading or nonphysiological condition. Finally, we propose Runx2 as a critical target gene in unloading to alter osteoblastic activity and bone formation in vivo.
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Masuda, Tatsuya, Hirohito Kubota, Naoya Sakuramoto, Asuka Hada, Ayaka Horiuchi, Asami Sasaki, Kanako Takeda i in. "RUNX-NFAT Axis As a Novel Therapeutic Target for AML and T Cell Immunity". Blood 136, Supplement 1 (5.11.2020): 25–26. http://dx.doi.org/10.1182/blood-2020-143458.
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Runt-related transcription factor (RUNX) transcription factors are essential regulators of diverse developmental processes. In mammals, there are three RUNX genes, RUNX1, RUNX2, and RUNX3. All RUNX proteins contain a highly conserved DNA-binding domain, called the runt-homology domain (RHD), which is responsible for DNA-binding and interaction with a partner, core binding factor subunit β (CBFβ). They regulate transcription of target genes, involving hematopoietic differentiation, cell cycle regulation, p53 pathways, and so on. From our previous studies, we assume that compensation mechanism is present among the RUNX family members. RUNX plays pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, common mechanism via RUNX in diverse acute myeloid leukemia (AML) remains elusive. Here, we demonstrate that targeting RUNX-nuclear factor of activated T cells 2 (NFATC2) axis is an effective strategy to suppress drug-resistant (DR)-acute promyelocytic leukemia (APL) cells. Silencing of RUNX and NFATC2 in DR-APL cells suppressed cell growth and induced apoptotic cell death. Next, by RNA-seq analysis of several AML patient cohorts, we confirmed that a strong positive correlation between RUNX family (RUNX1,2,3: Pan RUNX) and NFAT family (NFATC1,2,3,4, NFAT5: Pan NFAT) exists not only in APL but also in all hematopoietic malignancies and that AML forms the Pan RUNX high-Pan NFAT high expression cluster. Inspection of the NFATC1-3 promoter revealed the RUNX binding sequence, and direct transcriptionally regulation of NFATC1-3 by RUNX family was confirmed in both chromatin immunoprecipitation (ChIP)-seq analysis and dual luciferase reporter assay. We believe that RUNX-NFAT axis could be an important target in diverse AML. Next, considering the well-established role of RUNX and NFATC2 in T cell immunity, we also apply targeting RUNX-NFATC2 strategy to suppress T cell activation and xenogeneic graft-versus-host disease (GVHD).The expansion of donor T cells requires IL-2, and aGVHD has been defined as a Th1-mediated disease. It is now well known that RUNX, especially RUNX1 and RUNX3 , are highly expressed in T cells, and directly regulate Th1 cytokine genes. As immunosuppressive approach for the prevention or treatment of aGVHD, calcineurin inhibitors, cyclosporine A and tacrolimus, inhibit GVHD by preventing the activation of NFAT, and steroid inhibits transcription of proinflammatory genes. We suppose that targeting RUNX can downregulate NFAT and also cytokine genes in T cell. RUNX1 knockdown and PanRUNX knockdown led to deceased NFATC2 and cytokine gene expression in cytokine-producing Jurkat cell line. It was also confirmed that by inhibiting the RUNX family and suppressing the NFATC2 family at the transcriptional level, the amount of the total NFATC family was significantly reduced compared with the drug that suppresses the nuclear translocation of NFATc2.The importance of RUNX-NFATC2 axis in T cell immunity was also exactly confirmed by the rescue experiments. Finally, to achieve "cluster regulation of RUNX (CROX)" strategy, we have been developing a novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole (PI) polyamides (Chb-M') that targets consensus RUNX-binding sequences, and specifically inhibits binding of RUNX family members. So, Chb-M' can switch off the RUNX target genes efficiently. In diverse AML including APL, core binding factor (CBF)-AML, mixed lineage leukemia (MLL)-rearranged AML, and AML-M0 and so on, Chb-M' was remarkably effective, and suppressed the expression of NFAT family in the protein level and induced apoptotic cell death. ChbM' also had a prominent effect in the AMLPDX model.The importance of RUNX-NFAT axis in AML was confirmed by the pharmacological rescue experiments using phorbol 12-myristate 13-acetate (PMA) and Ionomycin stimulation. Chb-M' also suppressed NFATC2 and cytokine gene expression in peripheral blood mononuclear cells (PBMC) and ameliorated GVHD for xenogeneic GVHD mouse model by transplanting human PBMC into immunodeficient mice. Taken together, we show RUNX could be a novel therapeutic target against diverse AML and GVHD through targeting RUNX-NFAT axis. Disclosures No relevant conflicts of interest to declare.
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Li, Xueni, Mei Huang, Huiling Zheng, Yinyin Wang, Fangli Ren, Yu Shang, Yonggong Zhai i in. "CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation". Journal of Cell Biology 181, nr 6 (9.06.2008): 959–72. http://dx.doi.org/10.1083/jcb.200711044.
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Runx2, an essential transactivator for osteoblast differentiation, is tightly regulated at both the transcriptional and posttranslational levels. In this paper, we report that CHIP (C terminus of Hsc70-interacting protein)/STUB1 regulates Runx2 protein stability via a ubiquitination-degradation mechanism. CHIP interacts with Runx2 in vitro and in vivo. In the presence of increased Runx2 protein levels, CHIP expression decreases, whereas the expression of other E3 ligases involved in Runx2 degradation, such as Smurf1 or WWP1, remains constant or increases during osteoblast differentiation. Depletion of CHIP results in the stabilization of Runx2, enhances Runx2-mediated transcriptional activation, and promotes osteoblast differentiation in primary calvarial cells. In contrast, CHIP overexpression in preosteoblasts causes Runx2 degradation, inhibits osteoblast differentiation, and instead enhances adipogenesis. Our data suggest that negative regulation of the Runx2 protein by CHIP is critical in the commitment of precursor cells to differentiate into the osteoblast lineage.
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Maillard, Ivan, Laleh Talebian, Zhe Li, Yalin Guo, Daisuke Sugiyama, Maren E. Speck, Warren S. Pear i Nancy A. Speck. "A Hypomorphic Cbfb Allele Reveals a Critical Dosage-Sensitive Function of Core Binding Factors at the Earliest Stages of T Cell Development." Blood 106, nr 11 (16.11.2005): 124. http://dx.doi.org/10.1182/blood.v106.11.124.124.
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Abstract The family of core binding factors includes the DNA-binding subunits Runx1-3 and the common non-DNA binding partner CBFβ. Runx1 and CBFβ are essential for the emergence of hematopoietic stem cells during fetal development, but not for stem cell maintenance during later ontogeny. Runx1 is also required for megakaryocyte differentiation, B cell development, and for the DN2 to DN3 transition in thymocyte development. Runx2/CBFβ are critical for normal osteogenesis, and Runx3 for CD4 silencing in CD8+ T cells, but their contribution to other steps of hematopoietic development is unknown. To examine the collective role of core binding factors in hematopoiesis, we generated a hypomorphic Cbfb allele (Cbfbrss). CBFβ protein levels were reduced by approximately 2–3 fold in fetuses homozygous for the Cbfbrss allele (Cbfbrss/rss), and 3–4 fold in fetuses carrying one hypomorphic and one knockout allele (Cbfbrss/−). Cbfbrss/rss and Cbfbrss/− fetuses had normal erythroid and B cell development, and relatively mild abnormalities in megakaryocyte and granulocyte differentiation. In contrast, T cell development was very sensitive to an incremental reduction of CBFβ levels: mature thymocytes were decreased in Cbfbrss/rss fetuses, and virtually absent in Cbfbrss/−fetuses. We next assessed the development of Cbfbrss/rss and Cbfbrss/− fetal liver progenitors after transplantation to irradiated adult recipients, in competition with wild-type (wt) bone marrow cells. Wt, Cbfbrss/rss and Cbfbrss/− fetal progenitors replenished the erythroid, myeloid and B cell compartments equally well. The overall development of Cbfbrss/rss T cells was preserved, although CD4 expression was derepressed in double negative thymocytes. In Cbfbrss/− chimeras, mature thymocytes were entirely derived from competitor cells. Furthermore, the developmental block in Cbfbrss/− progenitors was present at the earliest stages of T cell development within the DN1 (ETP) and DN2 subsets. Our data define a critical CBFβ threshold for normal T cell development, and they situate an essential role of core binding factors during the earliest stages of T cell development. In addition, early thymopoiesis appeared more severely affected by reduced CBFβ dosage than by the lack of Runx1 (Ichikawa et al., Nat Med 2004; Growney et al., Blood 2005), suggesting that Runx2/3 may contribute to core binding factor activity in the T cell lineage.
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Jonason, J. H., G. Xiao, M. Zhang, L. Xing i D. Chen. "Post-translational Regulation of Runx2 in Bone and Cartilage". Journal of Dental Research 88, nr 8 (sierpień 2009): 693–703. http://dx.doi.org/10.1177/0022034509341629.
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The Runx2 gene product is essential for mammalian bone development. In humans, Runx2 haploinsufficiency results in cleidocranial dysplasia, a skeletal disorder characterized by bone and dental abnormalities. At the molecular level, Runx2 acts as a transcription factor for genes expressed in hypertrophic chondrocytes and osteoblasts. Runx2 gene expression and protein function are regulated on multiple levels, including transcription, translation, and post-translational modification. Furthermore, Runx2 is involved in numerous protein-protein interactions, most of which either activate or repress transcription of target genes. In this review, we discuss expression of Runx2 during development as well as the post-translational regulation of Runx2 through modification by phosphorylation, ubiquitination, and acetylation.
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Zhang, You-you, Xi Li, Shu-wen Qian, Liang Guo, Hai-yan Huang, Qun He, Yuan Liu, Chun-gu Ma i Qi-Qun Tang. "Down-Regulation of Type I Runx2 Mediated by Dexamethasone Is Required for 3T3-L1 Adipogenesis". Molecular Endocrinology 26, nr 5 (1.05.2012): 798–808. http://dx.doi.org/10.1210/me.2011-1287.
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Abstract Runx2, a runt-related transcriptional factor family member, is involved in the regulation of osteoblast differentiation. Interestingly, it is abundant in growth-arrested 3T3-L1 preadipocytes and was dramatically down-regulated during adipocyte differentiation. Knockdown of Runx2 expression promoted 3T3-L1 adipocyte differentiation, whereas overexpression inhibited adipocyte differentiation and promoted the trans-differentiation of 3T3-L1 preadipocytes to bone cells. Runx2 was down-regulated specifically by dexamethasone (DEX). Only type I Runx2 was expressed in 3T3-L1 preadipocytes. Using luciferase assay and chromatin immunoprecipitation-quantitative PCR analysis, it was found that DEX repressed this type of Runx2 at the transcriptional level through direct binding of the glucocorticoid receptor (GR) to a GR-binding element in the Runx2 P2 promoter. Further studies indicated that GR recruited histone deacetylase 1 to the Runx2 P2 promoter which then mediated the deacetylation of histone H4 and down-regulated Runx2 expression. Runx2 might play its repressive role through the induction of p27 expression, which blocked 3T3-L1 adipocyte differentiation by inhibiting mitotic clonal expansion. Taken together, we identified Runx2 as a new downstream target of DEX and explored a new pathway between DEX, Runx2, and p27 which contributed to the mechanism of the 3T3-L1 adipocyte differentiation.