Disease relevance of Runx1

• Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma [1].
• Our results therefore suggest that deficiency of Runx1 can indeed predispose mice to hematopoietic malignancies [1].
• Virus-mediated overexpression of Runx1 in mouse embryonic mesenchymal cells resulted in a potent induction of the early chondrocyte differentiation markers but not the hypertrophy marker, type X collagen [2].
• Core-binding factor beta (CBFbeta, also called polyomavirus enhancer binding protein 2beta (PEBP2B)) is associated with an inversion of chromosome 16 and is associated with acute myeloid leukemia in humans [3].
• Although all Runx family members can interact with Cbfbeta (core-binding factor b, encoded by Cbfb), a role for Cbfbeta in bone development has not been demonstrated owing to lethality in Cbfb(-/-) mouse embryos at 12.5 days post coitum (d.p.c.) from hemorrhages and lack of definitive hematopoiesis [4].

Psychiatry related information on Runx1

• Heterozygous disruption of Runx1 in BXH2 mice resulted in a shortening of the latency period of leukaemia [5].

High impact information on Runx1

• We previously reported that mice with a deletion of an upstream regulatory element (URE) of the gene encoding PU.1 (Sfpi1) developed acute myeloid leukemia [6].
• Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation [7].
• Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes [8].
• We show here that binding sites for Runt domain transcription factors are essential for CD4 silencer function at both stages, and that different Runx family members are required to fulfill unique functions at each stage [8].
• Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFbeta [9].

Chemical compound and disease context of Runx1

• However, after treatment of newborn hMRP8-AML1-ETO transgenic mice and their wild-type littermates with a strong DNA-alkylating mutagen, N-ethyl-N-nitrosourea, 55% of transgenic mice developed AML and the other 45% of transgenic mice and all of the wild-type littermates developed acute T lymphoblastic leukemia [10].
• Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors [11].
• These conditions selected a 5-FU-resistant AML fraction that was evaluated for its capacity for long-term growth by transplantation into mice with severe combined immunodeficiency (SCID) and long-term culture in the quantitative cobblestone area-forming cell (CAFC) assay [12].
• Incubation of AML blasts with RAD001 induces only a small decrease in survival of the cells; however, when combined with Ara-C, RAD001 enhances the toxicity of Ara-C [13].
• Initial clinical trials in patients with refractory acute myeloid leukemia and CML in blast crisis have shown significant activity, suggesting that trials combining imatinib and FTIs are warranted [14].

Biological context of Runx1

• In addition, the Runx1-IRES-GFP knock-in mouse strain should prove valuable for investigation of Runx1 function in adult hematopoiesis [15].
• Involvement of Runx1 in the down-regulation of fetal liver kinase-1 expression during transition of endothelial cells to hematopoietic cells [16].
• By contrast, Runx1 is weakly expressed in early erythroid cells, and its expression is rapidly extinguished during later stages of erythropoiesis [15].
• These results provide novel insight into the role Runx1 during the development of hematopoietic cell lineages [16].
• In order to examine the hypothesis that decreased gene dosage of RUNX1 may be a critical event in the development of leukemia, we treated chimeric mice generated from Runx1(lacZ/lacZ) embryonic stem (ES) cells that have homozygous disruption of the Runx1 gene with N-ethyl-N-nitrosourea (ENU) [1].

Anatomical context of Runx1

• We established embryonic stem cell clones carrying the Venus gene, a modified version of yellow fluorescence protein, in the Runx1 locus and cultured them on OP9 cells [16].
• In peripheral T cells, Runx1 is differentially expressed, with CD4+ T cells expressing 2- to 3-fold higher levels of Runx1 than CD8+ cells [15].
• Here we show that Runx1 represses Flk-1 during the development of hemogenic endothelial cells into hematopoietic cells [16].
• Runx1 expression is induced during early B-cell development and is expressed at a uniform level during all subsequent stages of B-cell development [15].
• Within the thymus, Runx1 is expressed at the highest level in CD4-CD8- double-negative thymocytes [15].

Associations of Runx1 with chemical compounds

• We also provide evidence that relief of the negative effect of the AML1 sites is important for Ca(2+) activation of the GM-CSF promoter/enhancer and that AML1 overexpression increases this Ca(2+) activation [17].
• In the t(8;21) translocation associated with acute myeloid leukemia (AML), the AML1(CBFA2/PEBP2alphaB) gene is juxtaposed to the MTG8(ETO/CDR) gene [18].
• We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate [19].
• Moreover, treatment of AML-1-ETO-expressing cells with trichostatin A, an HDAC inhibitor, restored cell cycle control [20].
• Northern blot analysis indicated the expression of human PEBP2 alpha A, alpha B (AML1), and beta genes in Jurkat cells [21].
• Consistent with this, we found that constitutive activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model [22].

Physical interactions of Runx1

• Gel retardation and reporter assays revealed that Runx1 binds to the promoter region of mouse IGFBP-3 gene and represses its transcription [23].
• These mutations result in the expression of fusion proteins that act dominant-negatively to suppress the normal function of the Runt-related transcription factor 1 (RUNX)/core binding factor beta (CBFbeta) complexes [1].
• The transcription factor Cbf beta forms a heterodimeric complex with members of the Runx family of proteins [24].
• AML1 contains a region of sequence homology to the Drosophila runt gene and the mouse polyomavirus enhancer binding protein PEBP2 alpha gene [25].

Regulatory relationships of Runx1

• Runx1 is highly expressed during chondrogenesis in comparison with Runx2, and Runx1 gain of functions stimulated this process [2].
• Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3 [23].
• Runx1 was also intensely expressed in the midline epithelium of palatal shelves [26].
• Moreover, dominant-negative Runx proteins can inhibit both activation of an OPN promoter reporter in transient transfections and expression of the endogenous OPN gene in mammary epithelial cells [27].
• The recognition that AML-1 interacts with mSin3A to repress transcription suggested that the inv(16) fusion protein might also repress the transcription of AML-1-target genes [28].

Other interactions of Runx1

• EBF function was enhanced by interaction with the transcription factor Runx1 [29].
• Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription [29].
• The models that have been developed should prove to be of value for defining the range of mutations that can cooperate with AML1/CBFbeta fusion proteins, and for assessing novel therapies targeted toward the pathways that are altered by the expression of these fusion proteins [30].
• The runt family transcription factors Runx1 and Runx3 are expressed in developing murine thymocytes [31].
• Overall, the expression of Runx1 remained significantly higher than Runx2 mRNA levels during early limb bud cell maturation [2].

Analytical, diagnostic and therapeutic context of Runx1

• We studied the regulation of Runx1 during chondrocyte differentiation by real-time RT-PCR and its function during chondrogenesis using overexpression and RNA interference [2].
• RESULTS: Immunohistochemistry showed that Runx1 and Runx2 are co-expressed in undifferentiated mesenchyme, had similar levels in chondrocytes undergoing transition from proliferation to hypertrophy, and that there was primarily Runx2 expression in hypertrophic chondrocytes [2].
• In situ hybridization using Runx1 and Runx2 specific probes indicate that both factors are expressed in mesenchymal stem cell progenitors during early embryonic development [32].
• Here, the crystallization of the Runx1 runt domain is reported [33].
• 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 [34].

References