Artykuły w czasopismach: „RUNX”

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Chuang, Linda Shyue Huey, Jian Ming Khor, Soak Kuan Lai, Shubham Garg, Vaidehi Krishnan, Cheng-Gee Koh, Sang Hyun Lee i Yoshiaki Ito. "Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression". Proceedings of the National Academy of Sciences 113, nr 23 (23.05.2016): 6490–95. http://dx.doi.org/10.1073/pnas.1523157113.

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The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity.

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Shin, Boyoung, Hiroyuki Hosokawa, Maile Romero-Wolf, Wen Zhou, Kaori Masuhara, Victoria R. Tobin, Ditsa Levanon, Yoram Groner i Ellen V. Rothenberg. "Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching". Proceedings of the National Academy of Sciences 118, nr 4 (21.01.2021): e2019655118. http://dx.doi.org/10.1073/pnas.2019655118.

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Runt domain-related (Runx) transcription factors are essential for early T cell development in mice from uncommitted to committed stages. Single and double Runx knockouts via Cas9 show that target genes responding to Runx activity are not solely controlled by the dominant factor, Runx1. Instead, Runx1 and Runx3 are coexpressed in single cells; bind to highly overlapping genomic sites; and have redundant, collaborative functions regulating genes pivotal for T cell development. Despite stable combined expression levels across pro-T cell development, Runx1 and Runx3 preferentially activate and repress genes that change expression dynamically during lineage commitment, mostly activating T-lineage genes and repressing multipotent progenitor genes. Furthermore, most Runx target genes are sensitive to Runx perturbation only at one stage and often respond to Runx more for expression transitions than for maintenance. Contributing to this highly stage-dependent gene regulation function, Runx1 and Runx3 extensively shift their binding sites during commitment. Functionally distinct Runx occupancy sites associated with stage-specific activation or repression are also distinguished by different patterns of partner factor cobinding. Finally, Runx occupancies change coordinately at numerous clustered sites around positively or negatively regulated targets during commitment. This multisite binding behavior may contribute to a developmental “ratchet” mechanism making commitment irreversible.

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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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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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Chuang, Linda Shyue Huey, Junichi Matsuo, Daisuke Douchi, Nur Astiana Bte Mawan i Yoshiaki Ito. "RUNX3 in Stem Cell and Cancer Biology". Cells 12, nr 3 (25.01.2023): 408. http://dx.doi.org/10.3390/cells12030408.

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The runt-related transcription factors (RUNX) play prominent roles in cell cycle progression, differentiation, apoptosis, immunity and epithelial–mesenchymal transition. There are three members in the mammalian RUNX family, each with distinct tissue expression profiles. RUNX genes play unique and redundant roles during development and adult tissue homeostasis. The ability of RUNX proteins to influence signaling pathways, such as Wnt, TGFβ and Hippo-YAP, suggests that they integrate signals from the environment to dictate cell fate decisions. All RUNX genes hold master regulator roles, albeit in different tissues, and all have been implicated in cancer. Paradoxically, RUNX genes exert tumor suppressive and oncogenic functions, depending on tumor type and stage. Unlike RUNX1 and 2, the role of RUNX3 in stem cells is poorly understood. A recent study using cancer-derived RUNX3 mutation R122C revealed a gatekeeper role for RUNX3 in gastric epithelial stem cell homeostasis. The corpora of RUNX3R122C/R122C mice showed a dramatic increase in proliferating stem cells as well as inhibition of differentiation. Tellingly, RUNX3R122C/R122Cmice also exhibited a precancerous phenotype. This review focuses on the impact of RUNX3 dysregulation on (1) stem cell fate and (2) the molecular mechanisms underpinning early carcinogenesis.

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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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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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Klunker, Sven, Mark M. W. Chong, Pierre-Yves Mantel, Oscar Palomares, Claudio Bassin, Mario Ziegler, Beate Rückert i in. "Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells". Journal of Experimental Medicine 206, nr 12 (16.11.2009): 2701–15. http://dx.doi.org/10.1084/jem.20090596.

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Forkhead box P3 (FOXP3)+CD4+CD25+ inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4+ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4+ T cells into Foxp3+ iT reg cells was significantly decreased in adoptively transferred CbfbF/F CD4-cre naive T cells into Rag2−/− mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and CbfbF/F CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4+ CD25high CD127− T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-β mRNA compared with CD4+CD25− cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-β–induced Foxp3 expression in iT reg cell differentiation and function.

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Ando, Kiyohiro, i Akira Nakagawara. "The RUNX Family Defines Trk Phenotype and Aggressiveness of Human Neuroblastoma through Regulation of p53 and MYCN". Cells 12, nr 4 (8.02.2023): 544. http://dx.doi.org/10.3390/cells12040544.

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The Runt-related transcription factor (RUNX) family, which is essential for the differentiation of cells of neural crest origin, also plays a potential role in neuroblastoma tumorigenesis. Consecutive studies in various tumor types have demonstrated that the RUNX family can play either pro-tumorigenic or anti-tumorigenic roles in a context-dependent manner, including in response to chemotherapeutic agents. However, in primary neuroblastomas, RUNX3 acts as a tumor-suppressor, whereas RUNX1 bifunctionally regulates cell proliferation according to the characterized genetic and epigenetic backgrounds, including MYCN oncogenesis. In this review, we first highlight the current knowledge regarding the mechanism through which the RUNX family regulates the neurotrophin receptors known as the tropomyosin-related kinase (Trk) family, which are significantly associated with neuroblastoma aggressiveness. We then focus on the possible involvement of the RUNX family in functional alterations of the p53 family members that execute either tumor-suppressive or dominant-negative functions in neuroblastoma tumorigenesis. By examining the tripartite relationship between the RUNX, Trk, and p53 families, in addition to the oncogene MYCN, we endeavor to elucidate the possible contribution of the RUNX family to neuroblastoma tumorigenesis for a better understanding of potential future molecular-based therapies.

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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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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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Akhtar, Md Naushad, Manish Mishra, Vinod Yadav, Manisha Yadav, Ravindra Gujar, Sunaina Lal, Raj Kumar, Neeraj Khatri i Pradip Sen. "Runx proteins mediate protective immunity against Leishmania donovani infection by promoting CD40 expression on dendritic cells". PLOS Pathogens 16, nr 12 (28.12.2020): e1009136. http://dx.doi.org/10.1371/journal.ppat.1009136.

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The level of CD40 expression on dendritic cells (DCs) plays a decisive role in disease protection during Leishmania donovani (LD) infection. However, current understanding of the molecular regulation of CD40 expression remains elusive. Using molecular, cellular and functional approaches, we identified a role for Runx1 and Runx3 transcription factors in the regulation of CD40 expression in DCs. In response to lipopolysaccharide (LPS), tumor necrosis factor alpha (TNFα) or antileishmanial drug sodium antimony gluconate (SAG), both Runx1 and Runx3 translocated to the nucleus, bound to the CD40 promoter and upregulated CD40 expression on DCs. These activities of Runx proteins were mediated by the upstream phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Notably, LD infection attenuated LPS- or TNFα-induced CD40 expression in DCs by inhibiting PI3K-Akt-Runx axis via protein tyrosine phosphatase SHP-1. In contrast, CD40 expression induced by SAG was unaffected by LD infection, as SAG by blocking LD-induced SHP-1 activation potentiated PI3K-Akt signaling to drive Runx-mediated CD40 upregulation. Adoptive transfer experiments further showed that Runx1 and Runx3 play a pivotal role in eliciting antileishmanial immune response of SAG-treated DCs in vivo by promoting CD40-mediated type-1 T cell responses. Importantly, antimony-resistant LD suppressed SAG-induced CD40 upregulation on DCs by blocking the PI3K-Akt-Runx pathway through sustained SHP-1 activation. These findings unveil an immunoregulatory role for Runx proteins during LD infection.

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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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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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van Wijnen, Andre J., Gary S. Stein, J. Peter Gergen, Yoram Groner, Scott W. Hiebert, Yoshiaki Ito, Paul Liu, James C. Neil, Misao Ohki i Nancy Speck. "Nomenclature for Runt-related (RUNX) proteins". Oncogene 23, nr 24 (maj 2004): 4209–10. http://dx.doi.org/10.1038/sj.onc.1207758.

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Kubota, Hirohito, Kana Furuichi, Tatsuya Masuda, Toshiya Tatsuta, Hidefumi Hiramatsu, Junko Takita, Sugiyama Hiroshi, Souichi Adachi i Yasuhiko Kamikubo. "Therapeutic Targeting of RUNX-NFATC2 Axis for Acute Promyelocytic Leukemia and T Cell Immunity". Blood 134, Supplement_1 (13.11.2019): 3359. http://dx.doi.org/10.1182/blood-2019-126428.

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Runt-related transcription factor (RUNX) play pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, the role of RUNX remains elusive in acute promyelocytic leukemia (APL). Here, we demonstrate that targeting RUNX1-NFATC2 axis is effective strategy to suppress drug-resistant (DR)-APL cells. Considering the well-established roles 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). Firstly, to investigate whether RUNX1 is essential for APL proliferation and maintenance, we examined cell proliferation of all-trans retinoic acid (ATRA) resistant APL cell line, NB4, using shRNA-mediated knockdown of RUNX1. Profound knockdown of RUNX1 in NB4 cells led to growth suppression and apoptotic cell death. We found that NFATC2 is one of the most consistently up-regulated genes in RUNX1-high expressing APL cells derived from previously reported human clinical samples (GSE2550, GSE13159, GSE61804), and also has RUNX1-binding regions in the promoter from chromatin-immunoprecipitation and sequencing (ChIP-Seq) data (GSE22178, GSE31221). ChIP qPCR assay confirmed the actual binding of RUNX1 in the NFATC2 promotor region of NB4. In addition, luciferase reporter experiments showed NFATC2 promoter significantly increased its reporter activity by RUNX1 over-expression. These results confirmed RUNX1 directly upregulated NFATC2 transcriptional activity. Consistent with these findings, silencing of RUNX1 suppressed the expression of NFATC2. Besides, silencing of NFATC2 in NB4 cells suppressed cell growth and induced apoptotic cell death. Next, the efficacy of our novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole polyamide (Chb-M'), which specifically binds to the consensus RUNX-binding sequence, was examined for NB4. Chb-M' was remarkably more effective against NB4 (IC50 value at nM level) than ATRA and arsenic trioxide. Consistent with association between RUNX1 and NFATC2, Chb-M' suppressed the expression of NFATC2 of NB4. Furthermore, Chb-M′ suppressed NB4 proliferation and NFATC2 expression in xenograft tumor model. Since RUNX and NFATC2 are key regulators of T cell function, we next investigate whether targeting RUNX is also effective for T cell mediated diseases including GVHD. Previous reports showed that RUNX1 directly regulate Th1 cytokine genes such as IL2 and IFNG (Ono M et. al. Nature 2007). From public ChIp-Seq data (ENCODE project. Nature 2012), RUNX1 also binds to NFATC2 promotor region in mouse and human primary CD4 T cells and T-ALL cell line, Jurkat. To study the efficacy of Chb-M' for allo-reactive T-cell activation and proliferation, we performed mixed lymphocyte reaction from different healthy donors using thymidine uptake assay. Compared to control, Chb-M' significantly reduced T cell proliferation. To examine the effect of Chb-M' for T cell cytokine expression, we stimulated peripheral blood mononuclear cells (PBMC) with PMA-ionomycin and measured cytokine expression by quantitative PCR. Results showed that Chb-M'moderately but significantly reduced IL2 , TNF , IFNG and NFATC2 mRNA expression. To investigate whether RUNX is essential for cytokine and NFATC2 expression, we silenced RUNX family by shRNA-knockdown of Jurkat E6.1 cell line. Knockdown of RUNX family reduced IL2 , TNF and NFATC2 expression. These results indicated targeting RUNX-NFATC2 axis is also effective for T cell activation and cytokine expression. Finally, we examined in vivo effect of Chb-M' for xenogeneic GVHD mouse model by transplanting human PBMC onto immunodeficient mice. Compared to control, mice injected by Chb-M' showed almost no sign of GVHD assessed by clinical score and pathological score of lung and liver. Analysing peripheral blood of GVHD mice showed that especially CD4 T cell was decreased and GVHD-associated cytokines including TNF-α and GM-CSF were reduced in Chb-M' injected mice. Taken together, we have shown that RUNX transcriptionally upregulated NFATC2, which is essential for APL proliferation and T cell activation. RUNX-NFATC2 axis can be a novel therapeutic target against DR-APL and GVHD. Disclosures No relevant conflicts of interest to declare.

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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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Szmajda-Krygier, Dagmara, Adrian Krygier, Krzysztof Jamroziak, Anna Korycka-Wołowiec, Marta Żebrowska-Nawrocka i Ewa Balcerczak. "RUNX1 and RUNX3 Genes Expression Level in Adult Acute Lymphoblastic Leukemia—A Case Control Study". Current Issues in Molecular Biology 44, nr 8 (1.08.2022): 3455–64. http://dx.doi.org/10.3390/cimb44080238.

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The genetic factors of adult acute lymphoblastic leukemia (ALL) development are only partially understood. The Runt-Related Transcription Factor (RUNX) gene family play a crucial role in hematological malignancies, serving both a tumor suppressor and promoter function. The aim of this study was the assessment of relative RUNX1 and RUNX3 genes expression level among adult ALL cases and a geographically and ethnically matched control group. The relative RUNX1 and RUNX3 genes expression level was assessed by qPCR. The investigated group comprised 60 adult patients newly diagnosed with ALL. The obtained results were compared with a group of 40 healthy individuals, as well as clinical and hematological parameters of patients, and submitted for statistical analysis. ALL patients tend to have significantly higher RUNX1 gene expression level compared with controls. This observation is also true for risk group stratification where high-risk (HR) patients presented higher levels of RUNX1. A higher RUNX1 transcript level correlates with greater leukocytosis while RUNX3 expression is reduced in Philadelphia chromosome bearers. The conducted study sustains the hypothesis that both a reduction and increase in the transcript level of RUNX family genes may be involved in leukemia pathogenesis, although their interaction is complex. In this context, overexpression of the RUNX1 gene in adult ALL cases in particular seems interesting. Obtained results should be interpreted with caution. Further analysis in this research field is needed.

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19

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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20

Liu, Jing, Eun-Sil Park i Misung Jo. "Runt-Related Transcription Factor 1 Regulates Luteinized Hormone-Induced Prostaglandin-Endoperoxide Synthase 2 Expression in Rat Periovulatory Granulosa Cells". Endocrinology 150, nr 7 (2.04.2009): 3291–300. http://dx.doi.org/10.1210/en.2008-1527.

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Runt-related transcription factor 1 (RUNX1), a transcription factor, is transiently induced by the LH surge and regulates gene expression in periovulatory granulosa cells. Potential binding sites for RUNX are present in the 5′-flanking region of the Ptgs2 (prostaglandin-endoperoxide synthase 2) gene. Periovulatory Ptgs2 expression is essential for ovulation. In the present study, we investigated the role of RUNX1 in mediating the LH-induced expression of Ptgs2 in periovulatory granulosa cells. We first determined whether the suppression of Runx1 expression or activity affects Ptgs2 expression using cultured preovulatory granulosa cells isolated from immature rat ovaries primed with pregnant mare serum gonadotropin for 48 h. Knockdown of human chorionic gonadotropin-induced Runx1 expression by small interfering RNA or inhibition of endogenous RUNX activities by dominant-negative RUNX decreased human chorionic gonadotropin or agonist-stimulated Ptgs2 expression and transcriptional activity of Ptgs2 promoter reporter constructs. Results from chromatin immunoprecipitation assays revealed in vivo binding of endogenous RUNX1 to the Ptgs2 promoter region in rat periovulatory granulosa cells. Direct binding of RUNX1 to two RUNX-binding motifs in the Ptgs2 promoter region was confirmed by EMSA. The mutation of these two binding motifs resulted in decreased transcriptional activity of Ptgs2 promoter reporter constructs in preovulatory granulosa cells. Taken together, these findings provide experimental evidence that the LH-dependent induction of Ptgs2 expression results, in part, from RUNX1-mediated transactivation of the Ptgs2 promoter. The results of the present study assign potential significance for LH-induced RUNX1 in the ovulatory process via regulating Ptgs2 gene expression.

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21

Hall, Ashley, Kwangmin Choi, Wei Liu, Jonathan Rose, Chuntao Zhao, Yanan Yu, Youjin Na i in. "RUNX represses Pmp22 to drive neurofibromagenesis". Science Advances 5, nr 4 (kwiecień 2019): eaau8389. http://dx.doi.org/10.1126/sciadv.aau8389.

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Patients with neurofibromatosis type 1 (NF1) are predisposed to develop neurofibromas, but the underlying molecular mechanisms of neurofibromagenesis are not fully understood. We showed dual genetic deletion of Runx1 and Runx3 in Schwann cells (SCs) and SC precursors delayed neurofibromagenesis and prolonged mouse survival. We identified peripheral myelin protein 22 (Pmp22/Gas3) related to neurofibroma initiation. Knockdown of Pmp22 with short hairpin RNAs increased Runx1fl/fl;Runx3fl/fl;Nf1fl/fl;DhhCre tumor-derived sphere numbers and enabled significantly more neurofibroma-like microlesions on transplantation. Conversely, overexpression of Pmp22 in mouse neurofibroma SCs decreased cell proliferation. Mechanistically, RUNX1/3 regulated alternative promoter usage and induced levels of protein expression of Pmp22 to control SC growth. Last, pharmacological inhibition of RUNX/core-binding factor β (CBFB) activity significantly reduced neurofibroma volume in vivo. Thus, we identified a signaling pathway involving RUNX1/3 suppression of Pmp22 in neurofibroma initiation and/or maintenance. Targeting disruption of RUNX/CBFB interaction might provide a novel therapy for patients with neurofibroma.

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Egawa, Takeshi, Robert E. Tillman, Yoshinori Naoe, Ichiro Taniuchi i Dan R. Littman. "The role of the Runx transcription factors in thymocyte differentiation and in homeostasis of naive T cells". Journal of Experimental Medicine 204, nr 8 (23.07.2007): 1945–57. http://dx.doi.org/10.1084/jem.20070133.

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Members of the Runx family of transcriptional regulators are required for the appropriate expression of CD4 and CD8 at discrete stages of T cell development. The roles of these factors in other aspects of T cell development are unknown. We used a strategy to conditionally inactivate the genes encoding Runx1 or Runx3 at different stages of thymocyte development, demonstrating that Runx1 regulates the transitions of developing thymocytes from the CD4−CD8− double-negative stage to the CD4+CD8+ double-positive (DP) stage and from the DP stage to the mature single-positive stage. Runx1 and Runx3 deficiencies caused marked reductions in mature thymocytes and T cells of the CD4+ helper and CD8+ cytotoxic T cell lineages, respectively. Runx1-deficient CD4+ T cells had markedly reduced expression of the interleukin 7 receptor and exhibited shorter survival. In addition, inactivation of both Runx1 and Runx3 at the DP stages resulted in a severe block in development of CD8+ mature thymocytes. These results indicate that Runx proteins have important roles at multiple stages of T cell development and in the homeostasis of mature T cells.

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Morita, Ken, Shintaro Maeda, Kensho Suzuki, Hiroki Kiyose, Junichi Taniguchi, Pu Paul Liu, Hiroshi Sugiyama, Souichi Adachi i Yasuhiko Kamikubo. "Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions". Blood Advances 1, nr 18 (8.08.2017): 1440–51. http://dx.doi.org/10.1182/bloodadvances.2017007591.

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Key Points Moderate attenuation of RUNX1 expression upregulates total RUNX expressions and enhances leukemogenesis through RUNX-GSTA2-ROS axis. Inhibiting GSTA2 function in vivo prolongs the overall survival of AML mice with intermediate RUNX1 expressions.

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Pandey, Manoj K., Albert F. Magnusen, Mary A. McKay, Tsitsi C. Nyamajenjere, Betsy Ann DiPasquale, Daniel N. Magnusen, Reena Rani, David Witte, Gregory A. Grabowski i Jörg Köhl. "Complement activation causes oncogene expression in Gaucher disease". Journal of Immunology 202, nr 1_Supplement (1.05.2019): 181.9. http://dx.doi.org/10.4049/jimmunol.202.supp.181.9.

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Abstract GBA1 mutations lead to defective lysosomal glucocerebrosidase resulting in accumulation of glucosylceramide (GC) in Gaucher disease (GD). Patients with GD have an increased risk to develop B cell lymphomas. The exact mechanistic bases for this propensity remain elusive. Recently, we uncovered formation of GC-specific IgG autoantibodies in Gba1 D409V/knockout (Gba19V/−) mice, which recapitulate features of human GD, and in humans with untreated GD. In vivo formation of IgG-GC immune complexes induced massive complement activation and C5a generation. Importantly, C5a-mediated activation of its cognate C5a receptor 1 (C5aR1) on immune cells enhanced GC synthesis, thereby fueling GC accumulation and excess tissue recruitment and activation of inflammatory myeloid and lymphoid immune cells, leading to visceral tissue damage in GD. Here, the expression of Runt-related transcription factor 1 (RUNX-1) was determined in Gba19V/− mice, to evaluate if C5a/C5aR1 axis activation may control the development of lymphomas in GD. RUNX-1 is a member of the Runt oncogene family linked to hematologic malignancies. We determined RUNX-1 expression in tissue from C5aR1 sufficient (+/+) and deficient (−/−) Gba19V/− mice as well as strain-matched control WT and C5aR1−/− mice. Compared to WT, Gba19V/− mice had increased RUNX-1 expression. Strikingly, RUNX-1 expression was markedly downregulated in C5aR−/−Gba19V/− vs. C5aR1+/+Gba19V/− mice. Our findings suggest that the C5a-C5aR1 axis activation in GD drives RUNX1 expression as a novel mechanism to control the development of hematologic malignancies in GD that may be diminished by targeting the C5aR1 axis in GD.

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Miething, Cornelius, Rebekka Grundler, Claudia Mugler, Heike Pfeifer, Oliver Ottmann, Simone Barwisch, Michael Speicher, Christian Peschel i Justus Duyster. "The Transcription Factors RUNX1/AML1 and RUNX3/AML2 Protect Bcr-Abl-Transformed B-Cells from Imatinib Induced Apoptosis." Blood 106, nr 11 (16.11.2005): 540. http://dx.doi.org/10.1182/blood.v106.11.540.540.

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Abstract The Abl-tyrosine kinase inhibitor Imatinib efficiently targets the Bcr-Abl kinase and produces major cytogenetic responses in most patients with chronic phase CML. In contrast, patients with advanced stage CML or Ph+ ALL frequently become refractory to Imatinib treatment. Resistance arises predominantly from point mutations in the Abl-kinase region, Bcr-Abl amplification or clonal evolution due to secondary genetic aberrations. To screen for genes contributing to clonal evolution, we have employed retroviral insertional mutagenesis in a murine CML/ALL model to identify potential candidate genes leading to Imatinib resistance. We found proviral insertions near the RUNX3/AML2 promoter in Imatinib resistant leukemic clones, leading to upregulation of RUNX3 mRNA expression. To analyze the effects of high RUNX3 levels on Imatinib response, we expressed RUNX3 in a Bcr-Abl-transformed murine pre-B-cell line. Significantly, whereas there was no effect on Imatinib-mediated proliferation inhibition, the cells displayed a marked reduction of apoptosis. A RUNX3R193A mutant carrying a mutation in the DNA-binding domain of RUNX3 did not protect from apoptosis, indicating that transcriptional regulation by RUNX3 was required to induce the anti-apoptotic effects. To allow for a controlled activation of RUNX transcriptional activity and to extend our analysis to other members of the RUNX family of transcription factors, we constructed 4-OH-tamoxifen (TAM) inducible RUNX3/AML2- and RUNX1/AML1-Estrogen receptor (ER) fusion proteins. These fusion proteins readily translocated from the cytoplasm into the nucleus and activated a RUNX-dependent TCRß-luciferase construct upon addition of TAM. Using these constructs, we could demonstrate that activation of RUNX3 as well as RUNX1 protected Bcr-Abl-transformed Ba/F3 cells from Imatinib-induced apoptosis. Furthermore, we found that RUNX1 mRNA levels were significantly upregulated in patients with Ph+ ALL upon resistance development. Taken together, our data indicate that elevated RUNX3 or RUNX1 levels may contribute to Imatinib resistance in Bcr-Abl expressing leukemic cells.

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Li, Xiaodong, Matthew Decker i Jennifer J. Westendorf. "TEThered to Runx: Novel binding partners for runx factors". Blood Cells, Molecules, and Diseases 45, nr 1 (czerwiec 2010): 82–85. http://dx.doi.org/10.1016/j.bcmd.2010.03.002.

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Deltcheva, Elitza, i Rachael Nimmo. "RUNX transcription factors at the interface of stem cells and cancer". Biochemical Journal 474, nr 11 (10.05.2017): 1755–68. http://dx.doi.org/10.1042/bcj20160632.

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The RUNX1 transcription factor is a critical regulator of normal haematopoiesis and its functional disruption by point mutations, deletions or translocations is a major causative factor leading to leukaemia. In the majority of cases, genetic changes in RUNX1 are linked to loss of function classifying it broadly as a tumour suppressor. Despite this, several recent studies have reported the need for a certain level of active RUNX1 for the maintenance and propagation of acute myeloid leukaemia and acute lymphoblastic leukaemia cells, suggesting an oncosupportive role of RUNX1. Furthermore, in solid cancers, RUNX1 is overexpressed compared with normal tissue, and RUNX factors have recently been discovered to promote growth of skin, oral, breast and ovarian tumour cells, amongst others. RUNX factors have key roles in stem cell fate regulation during homeostasis and regeneration of many tissues. Cancer cells appear to have corrupted these stem cell-associated functions of RUNX factors to promote oncogenesis. Here, we discuss current knowledge on the role of RUNX genes in stem cells and as oncosupportive factors in haematological malignancies and epithelial cancers.

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Bruno, Ludovica, Luca Mazzarella, Maarten Hoogenkamp, Arnulf Hertweck, Bradley S. Cobb, Stephan Sauer, Suzana Hadjur i in. "Runx proteins regulate Foxp3 expression". Journal of Experimental Medicine 206, nr 11 (19.10.2009): 2329–37. http://dx.doi.org/10.1084/jem.20090226.

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Runx proteins are essential for hematopoiesis and play an important role in T cell development by regulating key target genes, such as CD4 and CD8 as well as lymphokine genes, during the specialization of naive CD4 T cells into distinct T helper subsets. In regulatory T (T reg) cells, the signature transcription factor Foxp3 interacts with and modulates the function of several other DNA binding proteins, including Runx family members, at the protein level. We show that Runx proteins also regulate the initiation and the maintenance of Foxp3 gene expression in CD4 T cells. Full-length Runx promoted the de novo expression of Foxp3 during inducible T reg cell differentiation, whereas the isolated dominant-negative Runt DNA binding domain antagonized de novo Foxp3 expression. Foxp3 expression in natural T reg cells remained dependent on Runx proteins and correlated with the binding of Runx/core-binding factor β to regulatory elements within the Foxp3 locus. Our data show that Runx and Foxp3 are components of a feed-forward loop in which Runx proteins contribute to the expression of Foxp3 and cooperate with Foxp3 proteins to regulate the expression of downstream target genes.

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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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Seo, Wooseok, Aneela Nomura i Ichiro Taniuchi. "The Roles of RUNX Proteins in Lymphocyte Function and Anti-Tumor Immunity". Cells 11, nr 19 (3.10.2022): 3116. http://dx.doi.org/10.3390/cells11193116.

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The Runt-related transcription factor (RUNX) family of proteins are crucial for many developmental and immuno-physiological processes. Their importance in cellular and tissue development has been repeatedly demonstrated as they are often found mutated and implicated in tumorigenesis. Most importantly, RUNX have now emerged as critical regulators of lymphocyte function against pathogenic infections and tumorigenic cells, the latter has now revolutionized our current understandings as to how RUNX proteins contribute to control tumor pathogenicity. These multifunctional roles of RUNX in mammalian immune responses and tissue homeostasis have led us to appreciate their value in controlling anti-tumor immune responses. Here, we summarize and discuss the role of RUNX in regulating the development and function of lymphocytes responding to foreign and tumorigenic threats and highlight their key roles in anti-tumor immunity.

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Seo, Wooseok, Tomokatsu Ikawa, Hiroshi Kawamoto i Ichiro Taniuchi. "Runx1–Cbfβ facilitates early B lymphocyte development by regulating expression of Ebf1". Journal of Experimental Medicine 209, nr 7 (4.06.2012): 1255–62. http://dx.doi.org/10.1084/jem.20112745.

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Although Runx and Cbfβ transcription factor complexes are involved in the development of multiple hematopoietic lineages, their precise roles in early mouse B lymphocyte differentiation remain elusive. In this study, we examined mouse strains in which Runx1, Runx3, or Cbfβ were deleted in early B lineage progenitors by an mb1-cre transgene. Loss of Runx1, but not Runx3, caused a developmental block during early B lymphopoiesis, resulting in the lack of IgM+ B cells and reduced VH to DJH recombination. Expression of core transcription factors regulating early B cell development, such as E2A, Ebf1, and Pax5, was reduced in B cell precursors lacking Runx1. We detected binding of Runx1–Cbfβ complexes to the Ebf1 proximal promoter, and these Runx-binding motifs were essential to drive reporter gene expression. Runx1-deficient pro-B cells harbored excessive amounts of the repressive histone mark H3K27 trimethylation in the Ebf1 proximal promoter. Interestingly, retroviral transduction of Ebf1, but not Pax5, into Runx1-deficient progenitors restored not only development of B220+ cells that underwent VH to DJH rearrangement but also expression of B lineage signature genes. Collectively, these results demonstrate that Runx1–Cbfβ complexes are essential to facilitate B lineage specification, in part via epigenetic activation of the Ebf1 gene.

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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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Ogawa, Eisaku, Tomohiro Edamitsu, Hidetaka Ohmori, Kazuyoshi Kohu, Mineo Kurokawa, Hiroshi Kiyonari, Masanobu Satake i Ryuhei Okuyama. "Transcription Factors Runx1 and Runx3 Suppress Keratin Expression in Undifferentiated Keratinocytes". International Journal of Molecular Sciences 23, nr 17 (2.09.2022): 10039. http://dx.doi.org/10.3390/ijms231710039.

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The Runt-related transcription factor (Runx) family has been suggested to play roles in stem cell regulation, tissue development, and oncogenesis in various tissues/organs. In this study, we investigated the possible functions of Runx1 and Runx3 in keratinocyte differentiation. Both Runx1 and Runx3 proteins were detected in primary cultures of mouse keratinocytes. Proteins were localized in the nuclei of undifferentiated keratinocytes but translocated to the cytoplasm of differentiated cells. The siRNA-mediated inhibition of Runx1 and Runx3 expression increased expression of keratin 1 and keratin 10, which are early differentiation markers of keratinocytes. In contrast, overexpression of Runx1 and Runx3 suppressed keratin 1 and keratin 10 expression. Endogenous Runx1 and Runx3 proteins were associated with the promoter sequences of keratin 1 and keratin 10 genes in undifferentiated but not differentiated keratinocytes. In mouse skin, the inhibition of Runx1 and Runx3 expression by keratinocyte-specific gene targeting increased the ratios of keratin 1- and keratin 10-positive cells in the basal layer of the epidermis. On the other hand, inhibition of Runx1 and Runx3 expression did not alter the proliferation capacity of cultured or epidermal keratinocytes. These results suggest that Runx1 and Runx3 likely function to directly inhibit differentiation-induced expression of keratin 1 and keratin 10 genes but are not involved in the regulation of keratinocyte proliferation.

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Dutta, Bibek, i Motomi Osato. "The RUNX Family, a Novel Multifaceted Guardian of the Genome". Cells 12, nr 2 (7.01.2023): 255. http://dx.doi.org/10.3390/cells12020255.

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The DNA repair machinery exists to protect cells from daily genetic insults by orchestrating multiple intrinsic and extrinsic factors. One such factor recently identified is the Runt-related transcription factor (RUNX) family, a group of proteins that act as a master transcriptional regulator for multiple biological functions such as embryonic development, stem cell behaviors, and oncogenesis. A significant number of studies in the past decades have delineated the involvement of RUNX proteins in DNA repair. Alterations in RUNX genes cause organ failure and predisposition to cancers, as seen in patients carrying mutations in the other well-established DNA repair genes. Herein, we review the currently existing findings and provide new insights into transcriptional and non-transcriptional multifaceted regulation of DNA repair by RUNX family proteins.

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35

Mahadeveraju, Sharvani, Young-Ho Jung i James W. Erickson. "Evidence That Runt Acts as a Counter-Repressor of Groucho During Drosophila melanogaster Primary Sex Determination". G3: Genes|Genomes|Genetics 10, nr 7 (26.05.2020): 2487–96. http://dx.doi.org/10.1534/g3.120.401384.

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Runx proteins are bifunctional transcription factors that both repress and activate transcription in animal cells. Typically, Runx proteins work in concert with other transcriptional regulators, including co-activators and co-repressors to mediate their biological effects. In Drosophila melanogaster the archetypal Runx protein, Runt, functions in numerous processes including segmentation, neurogenesis and sex determination. During primary sex determination Runt acts as one of four X-linked signal element (XSE) proteins that direct female-specific activation of the establishment promoter (Pe) of the master regulatory gene Sex-lethal (Sxl). Successful activation of SxlPe requires that the XSE proteins overcome the repressive effects of maternally deposited Groucho (Gro), a potent co-repressor of the Gro/TLE family. Runx proteins, including Runt, contain a C-terminal peptide, VWRPY, known to bind to Gro/TLE proteins to mediate transcriptional repression. We show that Runt’s VWRPY co-repressor-interaction domain is needed for Runt to activate SxlPe. Deletion of the Gro-interaction domain eliminates Runt-ability to activate SxlPe, whereas replacement with a higher affinity, VWRPW, sequence promotes Runt-mediated transcription. This suggests that Runt may activate SxlPe by antagonizing Gro function, a conclusion consistent with earlier findings that Runt is needed for Sxl expression only in embryonic regions with high Gro activity. Surprisingly we found that Runt is not required for the initial activation of SxlPe. Instead, Runt is needed to keep SxlPe active during the subsequent period of high-level Sxl transcription suggesting that Runt helps amplify the difference between female and male XSE signals by counter-repressing Gro in female, but not in male, embryos.

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Telfer, Janice C., Nancy Malcuit, Emmett Hedblom i Christyne Kane. "Runx1/AML1 and hematopoietic dysplasia (84.6)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S116. http://dx.doi.org/10.4049/jimmunol.178.supp.84.6.

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Abstract We expressed several mutated forms of the Runx1 transcription factor in hematopoietic stem cells (HSC) and used them to reconstitute lethally irradiated mice. We found that the Runx1 mutant truncated shortly after the DNA-binding runt domain (Runx1.d190) transported appropriately to the nucleus and had strong dominant negative activity. Surprisingly, Runx1 mutants truncated before the runt DNA-binding site (Runx1.d49) also reiterated some of the effects of the Runx1.d190 dominant negative mutant, despite the lack of a nuclear localization site and DNA-binding capacity, suggesting that the N-terminus plays an active role in some Runx functions and that the N-terminal activity may be significant in Runx mutants lacking DNA-binding activity. The Runx1.d190 mutant, when expressed in HSC, results in the expansion of the cellular compartment containing HSC. In a competitive reconstitution in a lethally irradiated mouse, these Runx1.d190-positive cells and their progeny almost totally out-compete untransduced cells and their progeny. Some of the Runx1.d190-positive hematopoietic stem cells are able to reconstitute a sub-lethally irradiated mouse in all hematopoietic lineages and maintain that reconstitution for over a year, indicating transformation of a hematopoietic stem cell or its immediate progeny. The progeny of the Runx1.d190-positive hematopoietic stem cells are defective in several lineages, such as B cells, T cells, neutrophils, megakaryocytes, and erythrocytes. There is a significant loss of erythropoiesis in the bone marrow and the occurrence of splenic extramedullary hematopoiesis.

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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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Kim, Kwang-Youn, Tae Woo Oh, Jin-Yeul Ma i Kwang-Il Park. "Ethanol Extract ofLycopus lucidusTurcz. ex Benth Inhibits Metastasis by Downregulation of Runx-2 in Mouse Colon Cancer Cells". Evidence-Based Complementary and Alternative Medicine 2018 (19.07.2018): 1–8. http://dx.doi.org/10.1155/2018/9513290.

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Lycopus lucidusTurcz. ex Benth (LT) has been broadly used as a traditional medicinal herb in Asia including Korea, China, and Japan due to its noted ability to promote blood circulation and remove blood stasis. However, its anticancer mechanism is not understood. This study aims to elucidate the effects of ethanol extracts of LT (ELT) relative to the role of Runt-related transcription factor- (Runx-) 2 in the invasive and metastatic potentials of mouse colon cancer to determine the underlying mechanisms involved. ELT was evaluated for the antimetastasis activity using CT-26 colon cancer using wound healing, transwell matrigel, and western blot analysis. We used Runx-2-specific siRNA to further determine the relationship between Runx-2 and matrix metalloprotease- (MMP-) 9 in the migration and invasion of CT-26 cells. Runx-2 was first demonstrated to be a transcription factor that plays a remarkable role in diverse biological processes of chondrocytes and osteoblasts, but recently, Runx-2 has been reported to be associated with the progression of certain human cancers. ELT was not altered in its effects on growth inhibition. However, ELT significantly inhibited wound closure and cell invasion in a dose-dependent manner. ELT decreased the metastasis by regulating the activity of MMP-9 and Runx-2 at the translational levels. Our results demonstrate that ELT decreases metastasis by inhibiting the Runx-2–MMP-9 axis. We suggest that it can be used as a novel agent in therapeutic strategies for combating colon cancer.

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Walrad, Pegine B., Saiyu Hang, Genevieve S. Joseph, Julia Salas i J. Peter Gergen. "Distinct Contributions of Conserved Modules to Runt Transcription Factor Activity". Molecular Biology of the Cell 21, nr 13 (lipiec 2010): 2315–26. http://dx.doi.org/10.1091/mbc.e09-11-0953.

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Runx proteins play vital roles in regulating transcription in numerous developmental pathways throughout the animal kingdom. Two Runx protein hallmarks are the DNA-binding Runt domain and a C-terminal VWRPY motif that mediates interaction with TLE/Gro corepressor proteins. A phylogenetic analysis of Runt, the founding Runx family member, identifies four distinct regions C-terminal to the Runt domain that are conserved in Drosophila and other insects. We used a series of previously described ectopic expression assays to investigate the functions of these different conserved regions in regulating gene expression during embryogenesis and in controlling axonal projections in the developing eye. The results indicate each conserved region is required for a different subset of activities and identify distinct regions that participate in the transcriptional activation and repression of the segmentation gene sloppy-paired-1 (slp1). Interestingly, the C-terminal VWRPY-containing region is not required for repression but instead plays a role in slp1 activation. Genetic experiments indicating that Groucho (Gro) does not participate in slp1 regulation further suggest that Runt's conserved C-terminus interacts with other factors to promote transcriptional activation. These results provide a foundation for further studies on the molecular interactions that contribute to the context-dependent properties of Runx proteins as developmental regulators.

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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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Yamamoto, Etsuko, Yoshiki Arakawa, Youhei Mineharu, Masamitsu Mikami, Yasuzumi Matsui, Hiroshi Sugiyama, Susumu Miyamoto, Souichi Adachi i Yasuhiko Kamikubo. "ET-06 Suppression of glioblastoma through novel drug based on “Gene Switch Technology”". Neuro-Oncology Advances 2, Supplement_3 (1.11.2020): ii6. http://dx.doi.org/10.1093/noajnl/vdaa143.026.

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Abstract Glioblastoma (GBM) is the most common and aggressive malignancy primarily affecting adults. Despite intensive multimodal therapies, the prognosis of GBM is dismal and a novel therapy is needed. Here, we focused on RUNX, a transcription factor involved in the malignant transformation of GBM, and developed a novel Chlorambucil-conjugated PI-polyamides (Chb-M’), which “switches off” RUNX family. Chb-M’ specifically recognizes the consensus RUNX-binding sequences (TGTGGT) and alkylates it to inhibit transcription of the downstream gene of RUNX family. Chb-M’ has been shown to induce apoptosis and suppress proliferation in a variety of cancers including leukemia, and in this study, similar results were found for glioblastoma cells in vitro. Specific inhibition of RUNX1 led to a marked inhibition of tumor growth through cell cycle arrest and apoptosis. By using apoptosis array, we isolated several candidate genes which regulated by RUNX1. And some types of glioblastoma cell lines treated with Chb-M’ showed elevated expression of p21 and decreased survivin. From in silico analysis using glioma patient cohorts, survivin expression was significantly higher in GBM and it was possibly involved in maintaining the malignancy of GBM. Mechanistically survivin was found to be directly transcriptionally regulated by RUNX1 through ChIP assay and reporter assay. In addition, survivin K/D cells upregulated p21 expression and accelerated apoptosis. Taken together, we hypothesized that the RUNX1-survivin-p21 pathway can potentially be exploited in the management of this malignancy. Chb-M’ mediated regulation of RUNX1 can be a novel therapeutic strategy against GBM.

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Lee, You Mie. "RUNX Family in Hypoxic Microenvironment and Angiogenesis in Cancers". Cells 11, nr 19 (1.10.2022): 3098. http://dx.doi.org/10.3390/cells11193098.

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The tumor microenvironment (TME) is broadly implicated in tumorigenesis, as tumor cells interact with surrounding cells to influence the development and progression of the tumor. Blood vessels are a major component of the TME and are attributed to the creation of a hypoxic microenvironment, which is a common feature of advanced cancers and inflamed premalignant tissues. Runt-related transcription factor (RUNX) proteins, a transcription factor family of developmental master regulators, are involved in vital cellular processes such as differentiation, proliferation, cell lineage specification, and apoptosis. Furthermore, the RUNX family is involved in the regulation of various oncogenic processes and signaling pathways as well as tumor suppressive functions, suggesting that the RUNX family plays a strategic role in tumorigenesis. In this review, we have discussed the relevant findings that describe the crosstalk of the RUNX family with the hypoxic TME and tumor angiogenesis or with their signaling molecules in cancer development and progression.

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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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Osato, Motomi, Namiko Yamashita, Masatoshi Yanagida, Liqun Huang, Scott Kogan, Masayuki Iwasaki, Takuro Nakamura, Katsuya Shigesada, Norio Asou i Yoshiaki Ito. "Identification of Cooperating Genetic Alterations in RUNX Leukemia Using the Mouse Model for the Human Familial Leukemia, FPD/AML." Blood 104, nr 11 (16.11.2004): 3383. http://dx.doi.org/10.1182/blood.v104.11.3383.3383.

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Abstract The RUNX1/AML1 gene is essential for hematopoiesis and is most frequently involved in human leukemias. Loss-of-function of RUNX1 is the common underlying mechanism of RUNX leukemias: those carrying t(8;21), inv(16) and RUNX1 point mutations. As the weakest mode, haploinsufficiency of RUNX1/AML1 causes familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). Mice heterozygous for Runx1 null mutation, Runx1+/−, appear genetically equivalent to human FPD/AML patients, but showed no apparent defects and did not develop spontaneous leukemia, implying that additional genetic alterations are required for leukemia. To identify such abnormalities, retroviral insertional mutagenesis was employed by using BXH2 mice that have spontaneously transmittable ecotropic retrovirus. BXH2-Runx1+/− mice showed a shorter disease latency and more myeloid-specific phenotype than wild-type littermates. Therefore, BXH2-Runx1+/− mice appear to serve as the mouse model for FPD/AML to investigate myeloid leukemia. The genes selectively affected in BXH2-Runx1+/− mice by retroviral integration are likely to cooperate with Runx1+/−. c-Kit locus was involved twice in 24 BXH2-Runx1+/− but neither in 17 wild-type littermates nor in 135 inbred BXH2 mice reported in the RTCGD database, suggesting that c-KIT mutation cooperates with RUNX alteration in human leukemia. In fact, constitutively active mutants of c-KIT or functionally equivalent FLT3, were found in 10 out of 25 (40%) of human RUNX leukemias. Together, BXH2-Runx1+/− system appears useful to identify the genes cooperating with RUNX1 abnormalities.

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Estevez, Brian, Sara Borst, Danuta Jarocha, Varun Sudunagunta, Michael Gonzalez, James Garifallou, Hakon Hakonarson i in. "RUNX-1 haploinsufficiency causes a marked deficiency of megakaryocyte-biased hematopoietic progenitor cells". Blood 137, nr 19 (13.05.2021): 2662–75. http://dx.doi.org/10.1182/blood.2020006389.

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Abstract Patients with familial platelet disorder with a predisposition to myeloid malignancy (FPDMM) harbor germline monoallelic mutations in a key hematopoietic transcription factor, RUNX-1. Previous studies of FPDMM have focused on megakaryocyte (Mk) differentiation and platelet production and signaling. However, the effects of RUNX-1 haploinsufficiency on hematopoietic progenitor cells (HPCs) and subsequent megakaryopoiesis remains incomplete. We studied induced pluripotent stem cell (iPSC)–derived HPCs (iHPCs) and Mks (iMks) from both patient-derived lines and a wild-type (WT) line modified to be RUNX-1 haploinsufficient (RUNX-1+/−), each compared with their isogenic WT control. All RUNX-1+/− lines showed decreased iMk yield and depletion of an Mk-biased iHPC subpopulation. To investigate global and local gene expression changes underlying this iHPC shift, single-cell RNA sequencing was performed on sorted FPDMM and control iHPCs. We defined several cell subpopulations in the Mk-biased iHPCs. Analyses of gene sets upregulated in FPDMM iHPCs indicated enrichment for response to stress, regulation of signal transduction, and immune signaling-related gene sets. Immunoblot analyses in FPDMM iMks were consistent with these findings, but also identified augmented baseline c-Jun N-terminal kinase (JNK) phosphorylation, known to be activated by transforming growth factor-β1 (TGF-β1) and cellular stressors. These findings were confirmed in adult human CD34+-derived stem and progenitor cells (HSPCs) transduced with lentiviral RUNX1 short hairpin RNA to mimic RUNX-1+/−. In both iHPCs and CD34+-derived HSPCs, targeted inhibitors of JNK and TGF-β1 pathways corrected the megakaryopoietic defect. We propose that such intervention may correct the thrombocytopenia in patients with FPDMM.

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Illendula, Anuradha, Jane Gilmour, Jolanta Grembecka, Venkata Sesha Srimath Tirumala, Adam Boulton, Aravinda Kuntimaddi, Charles Schmidt i in. "Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers". EBioMedicine 8 (czerwiec 2016): 117–31. http://dx.doi.org/10.1016/j.ebiom.2016.04.032.

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Jenkins, Christopher R., Hongfang Wang, Olena O. Shevchuk, Sonya H. Lam, Vincenzo Giambra, Louis Wang, Samuel D. Gusscott, Jon C. Aster i Andrew P. Weng. "Collaboration Between RUNX and NOTCH Pathways in T-Cell Acute Lymphoblastic Leukemia". Blood 120, nr 21 (16.11.2012): 1279. http://dx.doi.org/10.1182/blood.v120.21.1279.1279.

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Abstract Abstract 1279 T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by the clonal outgrowth of developmentally arrested T-lymphoid blasts. Notch signaling is activated by mutation of NOTCH1 and/or FBW7 in over half of cases, and ultimately results in increased expression of target genes via the NOTCH/CSL transcriptional complex. Enforced expression of activated NOTCH1 in mouse hematopoietic progenitors leads to the development of clonal T-cell leukemias, suggesting that collaborating mutations are required for establishment and/or propagation of malignant clones. To identify candidate collaborating loci, Beverly and Capobianco performed a retroviral insertional mutagenesis screen in mice expressing a relatively weak activated Notch1 transgene and found recurrent insertions into Ikaros (Ikzf1). These insertions resulted in expression of dominant negative isoforms of Ikaros and thus potentiated Notch signaling since Ikaros and Notch/CSL compete for occupancy at target gene regulatory elements. In an attempt to identify collaborating mutations outside of the Notch pathway, we performed a similar screen, but employed instead a very potent activated NOTCH1 allele (ΔE) in hopes of saturating the Notch signaling pathway. We thus cloned out the insertion sites from 88 primary mouse leukemias generated by transduction of bone marrow with ΔE retrovirus. While recurrent insertions into Ikzf1 were again identified, we also observed frequent insertions into other regions including the Runx3 locus. The Runx3 integrations were tightly clustered in a region 40–60kb upstream of the transcriptional start site, suggesting the retroviral LTR might be inducing an increase in Runx3 expression. A single integration upstream of Runx1 was also identified in a region frequently mutated in similar screens. Of note, analysis of publically available gene expression profile data revealed that RUNX1 and RUNX3 are ubiquitously expressed in patient T-ALL samples. In order to functionally characterize the roles of RUNX1 and RUNX3 in T-ALL, we utilized lentiviral shRNAs to knock down RUNX1 and/or RUNX3 across a broad panel of 26 human T-ALL cell lines. Despite recent studies suggesting RUNX1 may act as a tumor suppressor in T-ALL, we observed the overwhelming majority of cell lines to show substantial growth defects after knock-down of RUNX1/3 as measured by competitive growth assay. These results were confirmed in a subset of cell lines and also in xenograft-expanded primary T-ALL samples by BrdU incorporation/DNA content assays which showed reduced proliferation/G1 cell cycle arrest following RUNX1/3 knock-down. Conversely, overexpression of RUNX3 induced T-ALL cells to proliferate more rapidly and to resist ABT-263-induced apoptosis. To explore potential target genes responsible for these pro-growth/survival effects, we mined available ChIP-Seq data and found NOTCH1/CSL and RUNX1 binding sites to co-localize within IGF1R and IL7R loci at intronic enhancer-like regions with associated H3K4me1>H3K4me3 marks and reduced H3K27me3 marks. Importantly, we show that NOTCH1 and RUNX factors co-regulate surface protein expression of IGF1R and IL7R in a synergistic/additive manner. As we and others have previously demonstrated important roles for both IGF1R and IL7R in T-ALL cell growth and leukemia-initiating activity, these studies reveal a novel collaborative mechanism between NOTCH1 and RUNX proteins in supporting propagation of established T-ALL disease. Disclosures: No relevant conflicts of interest to declare.

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Haley, Kathleen J., Jessica Lasky-Su, Sara E. Manoli, Lacey A. Smith, Aliakbar Shahsafaei, Scott T. Weiss i Kelan Tantisira. "RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking". American Journal of Physiology-Lung Cellular and Molecular Physiology 301, nr 5 (listopad 2011): L693—L701. http://dx.doi.org/10.1152/ajplung.00348.2010.

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Intrauterine smoke exposure (IUS) is a strong risk factor for development of airways responsiveness and asthma in childhood. Runt-related transcription factors (RUNX1–3) have critical roles in immune system development and function. We hypothesized that genetic variations in RUNX1 would be associated with airway responsiveness in asthmatic children and that this association would be modified by IUS. Family-based association testing analysis in the Childhood Asthma Management Program genome-wide genotype data showed that 17 of 100 RUNX1 single-nucleotide polymorphisms (SNPs) were significantly ( P < 0.03–0.04) associated with methacholine responsiveness. The association between methacholine responsiveness and one of the SNPs was significantly modified by a history of IUS exposure. Quantitative PCR analysis of immature human lung tissue with and without IUS suggested that IUS increased RUNX1 expression at the pseudoglandular stage of lung development. We examined these associations by subjecting murine neonatal lung tissue with and without IUS to quantitative PCR ( N = 4–14 per group). Our murine model showed that IUS decreased RUNX expression at postnatal days (P)3 and P5 ( P < 0.05). We conclude that 1) SNPs in RUNX1 are associated with airway responsiveness in asthmatic children and these associations are modified by IUS exposure, 2) IUS tended to increase the expression of RUNX1 in early human development, and 3) a murine IUS model showed that the effects of developmental cigarette smoke exposure persisted for at least 2 wk after birth. We speculate that IUS exposure-altered expression of RUNX transcription factors increases the risk of asthma in children with IUS exposure.

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Yi, Hongyang, Yuhao He, Qionghua Zhu i Liang Fang. "RUNX Proteins as Epigenetic Modulators in Cancer". Cells 11, nr 22 (20.11.2022): 3687. http://dx.doi.org/10.3390/cells11223687.

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RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis by cross-talking with different signaling pathways such as Wnt, TGF-β, and Hippo. Molecularly, they could serve as transcription factors (TFs) to activate their direct target genes or interact with many other TFs to modulate chromatin architecture globally. Here, we review the current knowledge on the functions and regulations of RUNX proteins in different cancer types and highlight their potential role as epigenetic modulators in cancer.

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Neil, James C., Gillian Borland i Anna Kilbey. "Addiction to RUNX in lymphoma". Aging 8, nr 9 (28.09.2016): 1832–33. http://dx.doi.org/10.18632/aging.101071.

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