Interplay between transcription regulators RUNX1 and FUBP1 activates an enhancer of the oncogene c-KIT and amplifies cell proliferation

Lydie Debaize, Hélène Jakobczyk, Stéphane Avner, Jérémie Gaudichon, Anne-Gaëlle Rio, Aurélien A Sérandour, Lena Dorsheimer, Frédéric Chalmel, Jason S Carroll, Martin Zörnig, Michael A Rieger, Olivier Delalande, Gilles Salbert, Marie-Dominique Galibert, Virginie Gandemer, Marie-Bérengère Troadec, Lydie Debaize, Hélène Jakobczyk, Stéphane Avner, Jérémie Gaudichon, Anne-Gaëlle Rio, Aurélien A Sérandour, Lena Dorsheimer, Frédéric Chalmel, Jason S Carroll, Martin Zörnig, Michael A Rieger, Olivier Delalande, Gilles Salbert, Marie-Dominique Galibert, Virginie Gandemer, Marie-Bérengère Troadec

Abstract

Runt-related transcription factor 1 (RUNX1) is a well-known master regulator of hematopoietic lineages but its mechanisms of action are still not fully understood. Here, we found that RUNX1 localizes on active chromatin together with Far Upstream Binding Protein 1 (FUBP1) in human B-cell precursor lymphoblasts, and that both factors interact in the same transcriptional regulatory complex. RUNX1 and FUBP1 chromatin localization identified c-KIT as a common target gene. We characterized two regulatory regions, at +700 bp and +30 kb within the first intron of c-KIT, bound by both RUNX1 and FUBP1, and that present active histone marks. Based on these regions, we proposed a novel FUBP1 FUSE-like DNA-binding sequence on the +30 kb enhancer. We demonstrated that FUBP1 and RUNX1 cooperate for the regulation of the expression of the oncogene c-KIT. Notably, upregulation of c-KIT expression by FUBP1 and RUNX1 promotes cell proliferation and renders cells more resistant to the c-KIT inhibitor imatinib mesylate, a common therapeutic drug. These results reveal a new mechanism of action of RUNX1 that implicates FUBP1, as a facilitator, to trigger transcriptional regulation of c-KIT and to regulate cell proliferation. Deregulation of this regulatory mechanism may explain some oncogenic function of RUNX1 and FUBP1.

Figures

Figure 1.
Figure 1.
RUNX1 ChIP-Seq signals are enriched within transcriptionally active chromatin regions. (A) Venn-diagrams presenting the intersection between RUNX1 binding regions in both replicates in Nalm6 cells, and bone marrow mononuclear cells isolated from three pre-B ALL patients. (B) Analyses of RUNX1 ChIP-Seq-enriched signals for pre-B Nalm6 cells and bone marrow mononuclear cells isolated from a pre-B acute lymphoblastic leukemia patient. ChIP-Seq reads were aligned to the reference human genome version GRCh37 (hg19). Analyses with the cis-regulatory Element Annotation System (CEAS) (47) software of RUNX1 ChIP-Seq provided RUNX1-bound regions enrichment in different genomic regions compared to the whole genome. (Ci and Cii) Read density plots for H3K4me1, H3K4me3 and H3K27ac enrichment centered around RUNX1 binding sites over a 3 kb window from RUNX1 Chip-Seq in Nalm6 cells, in promoter regions ([–4000 +1000] from TSS of annotated genes) (Ci) or without promoter regions (Cii). (D) Read density plots for RUNX1 signal around H3K4me1, H3K27ac, H3K4me3 regions over a 3 kb window and random regions of similar lengths in Nalm6 cells. The graph shows that the average RUNX1 signal peaked at regions positive for H3K4me3, H3K4me1 and H3K27ac. (E) Annotation enrichments of the 2651 potential RUNX1 target genes identified with DAVID (81) for biological process and GREAT (48) for disease ontology were shown. We selected 5 non-redundant annotations among the 10 most significant.
Figure 2.
Figure 2.
FUBP1 protein interacts with RUNX1 in hematopoietic lineages. (A) Number of peptides from RUNX1 (49 kDa), CBFB (22 kDa) and FUBP1 (68 kDa) proteins identified by RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins) with RUNX1 or immunoglobulin G (IgG) control in pre-B lymphoblastic Nalm6 cells. The lysates were incubated with 10 μg of anti-RUNX1 (ab23980, Abcam), 5 μg of anti-RUNX1 (HPA004176, Sigma Aldrich) or with 10 μg of normal anti-IgG (sc2027, Santa Cruz Biotechnology). (B) Co-immunoprecipitation (IP) using anti-Flag antibody (M2 clone) in HEK293 cells expressing Halotag-RUNX1 and/or Flag-FUBP1. Western blots were performed with RUNX1 and FUBP1 antibodies. Similar levels of IgG heavy chains in both IP-Flag lanes were used as loading control. (Ci) Representative images of a Proximity Ligation Assay (PLA) in Nalm6 cells. Four pairs of antibodies were used as indicated (references of the antibodies are listed in the Supplementary Table S1). Nuclei were stained by DAPI and appeared in blue. Colocalization of proteins, visualized by PLA dots, appeared in green. (Cii and Ciii) Quantitation of protein co-localization per nucleus–visualized by PLA dots- in Nalm6 cells, presented with the mean values ± S.D. The value of the mean is indicated at the top of each scatter dot plot. Quantitation of PLA dots was performed by an automatic counting with ImageJ as published by Debaize et al. (42). Positive controls (named total RUNX1 or total FUBP1, where primary antibodies against two different epitopes of RUNX1 or FUBP1 were used) and negative controls (either anti-RUNX1 alone or anti-FUBP1 alone) were included. Here, the positive threshold value represented by the dotted line (set at two S.D over the background signal) is 4.3 dots. One representative experiment of at least two independent experiments is shown. (Ciii) CBP and P300 are co-activators that are well known to interact with RUNX1. (D) Quantitation of protein colocalization per nucleus (visualized by PLA dots) in human mononuclear cells from bone marrow of three pre-B acute lymphoblastic leukemia patients, presented with the mean values. The value of the mean is indicated at the top of each scatter dot plot. Here, the positive threshold value represented by the dotted line is 1.7 dots.
Figure 3.
Figure 3.
FUBP1 and RUNX1 regulate c-KIT transcription by binding to a common intronic enhancer in the c-KIT gene. (A) Expression data analyses of c-KIT mRNA. RT-qPCR were performed in biological triplicate in Nalm6 cells overexpressing FUBP1 or RUNX1 (see Supplementary Figure S2A) and expression data are given compared to Nalm6control cells after normalizing with GAPDH mRNA (error bars are S.D.). *P < 0.05, **P < 0.01, ***P < 0.001 in Mann–Whitney tests. (B) Genomic tracks displayed ChIP-Seq data for RUNX1 and the histones H3K4me3, H3K27ac and H3K4me1 from Nalm6 cells (2 replicates) and bone marrow mononuclear cells isolated from three pre-B acute lymphoblastic leukemia patient across the first 35 kb of the human c-KIT gene (NM_000222). ChIP-Seq data were acquired by Illumina sequencing and visualized with Integrated Genome Browser 9.0.0 (82). ChIP-Seq reads were aligned to the reference human genome version GRCh37 (hg19). Both genomic regions of c-KIT gene that were associated with active histone marks are located within the first intron, one in a promoter region (+700 pb from TSS) and the another in an enhancer region (+30 kb from TSS) and are indicated by boxes. (C) ChIP-qPCR performed on samples from Nalm6 cells using a specific anti-RUNX1 (n = 3), anti-FUBP1 (n = 3) or a non-specific control IgG. ChIP-qPCR shows fold enrichment for c-KIT promoter (+700 pb) and enhancer (+30 kb) regulatory regions. Histogram indicates the means with S.D. of the fold enrichment of peaks relative to IgG. (D) Luciferase assays with a vector containing the c-KIT promoter or enhancer regions downstream a minimal promoter and a luciferase ORF, in presence of RUNX1 and FUBP1 expressing vectors in HEK293shFUBP1 cells (see Supplementary Figure S2E). Note that the HEK293shFUBP1 cells do not express RUNX1 and that the FUBP1 expression vector is resistant to shFUBP1. Luciferase levels (firefly luciferase/Renilla luciferase) are represented using a scatter dot plot indicating the means and S.D. of at least 4 independent experiments. NS: non-significant, * < 0.05 in Mann–Whitney tests. (E) Luciferase assays with a vector containing the c-KIT enhancer regions downstream a minimal promoter and a luciferase ORF, in presence of RUNX1 and FUBP1 expressing vectors in Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1 and Nalm6+RUNX1+FUBP1 cells. Luciferase levels are represented using a scatter dot plot indicating the means and S.D. of at least four independent experiments (i.e. each dot represents an independent stable cell line). The expression level of RUNX1 is similar in Nalm6+RUNX1 and Nalm6+RUNX1+FUBP1. The expression level of FUBP1 is similar in Nalm6+FUBP1 and Nalm6+RUNX1+FUBP1 (refer to Figure 6A, Supplementary Figure S3B). NS: non-significant, *P < 0.05 in Mann–Whitney tests.
Figure 4.
Figure 4.
FUBP1 is a facilitator of the binding of RUNX1 on the +30kb enhancer of c-KIT. (A) ChIP-qPCR performed on samples from Nalm6control and Nalm6shFUBP1 cells using a specific anti-RUNX1 (n = 3) or a non-specific control IgG (n = 3) at the c-KIT enhancer (+30 kb) regulatory regions. Histogram indicates the means with S.D. of the fold enrichment of peaks relative to IgG. (B) ChIP-qPCR performed on samples from Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1 and Nalm6+RUNX1+FUBP1 cells using specific anti-histones H3K4me3, H3K27ac and H3K4me1 at the c-KIT promoter (+700 bp) and enhancer (+30 kb) regulatory regions. Histogram indicates the fold enrichment of peaks relative to IgG.
Figure 5.
Figure 5.
Identification of RUNX1 and FUBP1 DNA binding motifs within the +30 kb enhancer of c-KIT. (A) Schematic representation of two functional subdomains (KH3 and KH4) of FUBP1 required for its binding to the FUSE sequence located –1.5 kb upstream the c-MYC P1 promoter (20,59). Potential c-KIT FUSE-like sequence within the +30 kb c-KIT intronic enhancer (identified by in silico analysis) is provided. Nucleic acid homology is represented by asterisks (*). The c-KIT FUSE-like sequence showed 48.2% homology compared to the FUSE sequence according to CLUSTAL 2.1 Multiple Sequence Alignments software (83). (Bi) Scheme of the human c-KIT enhancer. Predicted RUNX1 binding sites with more than 80% sequence conservation from Jaspar RUNX1 matrix (MA0002.1) have been selected with Jaspar software (61). (Bii) Luciferase assays with a vector full-length or mutated variants of the +30 kb c-KIT enhancer downstream a minimal promoter and a luciferase ORF, in presence of RUNX1 and FUBP1 expressing vectors were performed in HEK293shFUBP1 cells. In the mutated variants, RUNX1 predicted binding sites 5′-GGTGTTGTG-3′ and 5′-ATTGTGGTTA-3′ were site-directed mutated or the predicted FUBP1 FUSE-like binding sequence was deleted. Luciferase levels (firefly luciferase/Renilla luciferase) are represented using a bar chart-scatter dot plot indicating the means with S.D. of at least four independent experiments. Luciferase activities are normalized to the control (–). NS: non-significant, *P < 0.05 in Mann–Whitney tests. (Ci) Scheme of RUNX1 and FUBP1 proteins with indication of the position of mutations for RUNX1, and truncated FUBP1. ID: inhibition domain, TE/TD: transactivation domain. (Cii) Luciferase assays with a vector containing the +30 kb c-KIT enhancer downstream a minimal promoter and a luciferase ORF, in presence of RUNX1 mutants and truncated FUBP1 expressing vectors were performed in HEK293shFUBP1 cells. Luciferase levels are represented as in Bii.(Di) Binding energies (kcal.mol-1) of the KH3 subdomain of FUBP1 protein with the c-KIT FUSE-like sequence. Red framed sequence corresponds to the positioning of KH4 subdomain by analogy to the FUSE sequence retrieved on c-MYC promoter associated to the solution NMR structure of KH4 (PDB ID: 1J4W). Maximum binding energy of KH3 is computed for 5′-ATATAAA-3′. (Dii) Structural model for the most stable complex formed by the KH3 subdomain with the c-KIT +30 kb enhancer sequence. Protein is shown as a molecular surface colored according to hydrophobicity (84) (white for hydrophilic, yellow for hydrophobic), electrostatic potentials are represented as iso-surfaces (–50kTe in red and +50kTe in blue). Tilt observed between second (dT) and third (dA) bases originates from the position of the KH3 first alpha-helix, as it was observed in the experimental structure used as structural template for modeling. (Diii) Schematic representation of the amino-acids of KH3 subdomain of FUBP1 involved in the binding to the FUSE sequence.
Figure 6.
Figure 6.
FUBP1 and RUNX1 exacerbate the c-KIT pathway. (A) mRNA levels analyzed by RT-qPCR of c-KIT, FUBP1, and RUNX1 in Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1, and Nalm6+RUNX1+FUBP1 cells. Results are presented in terms of a fold change after normalizing with GAPDH mRNA. Each dot represents a biological replicate. NS: non-significant, **P < 0.01, ***P < 0.001, ****P < 0.0001 in Mann–Whitney tests. (B) Correlation between FUBP1 and KIT mRNA levels from different transduced Nalm6+FUBP1 and Nalm6+RUNX1+FUBP1 stable cell lines, and correlation between RUNX1 and KIT mRNA levels in Nalm6+RUNX1 and Nalm6+RUNX1+FUBP1 cells are presented. P-value (p), Pearson correlation coefficient (r), slope of the correlation curve (slope), and number of biological replicates analyzed (n) are indicated. (C) FACS analyses following c-KIT (CD117) intracellular and surface staining in Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1, or Nalm6+RUNX1+FUBP1 cells. The c-KIT expression was assessed in comparison with the control isotype staining. A representative analysis of the KIT surface staining is shown on the left. Percentage of the mean fluorescence intensity (MFI) is presented on the right panel (n = 4–8 per group) after normalizing with Nalm6control cells. Statistical significance was assessed compared to Nalm6control cells by Mann–Whitney tests (NS: non-significant, *P < 0.05, **P < 0.01, ***P < 0 .001). (D) Mean fluorescence intensity (MFI) analyzed by FACS from Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1, and Nalm6+RUNX1+FUBP1 cells following SCF treatment (0 or 100 ng/ml of SCF were added in the culture media and incubated 5 min at 37°C) and c-KIT surface staining. SCF induces c-KIT internalization and degradation, one of the hallmarks of c-KIT functionality (69). Statistical significance was assessed compared to untreated cells (without SCF) by Mann–Whitney tests (NS: non-significant, *P < 0.05, **P < 0.01, ***P < 0 .001).
Figure 7.
Figure 7.
FUBP1 and RUNX1 contribute to c-KIT-dependent cell proliferation. (A) Proliferation curves from Nalm6control (n = 5), Nalm6+RUNX1 (n = 4), Nalm6+FUBP1 (n = 5), Nalm6+RUNX1+FUBP1 (n = 5) cells exposed to 0 or 100 ng/ml of SCF the first day (day 0). Histogram (on the right) represents the number (means with S.D.) of cells at day 7. Statistical significance was assessed compared to Nalm6control by Mann–Whitney tests (NS: non-significant, *P < 0.05, **P < 0.01). (B) Survival curves from immunodeficient NOD/scid IL2 Rgnull mice xenografted with 100 000 cells: Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1, or Nalm6+RUNX1+FUBP1 human cell lines (n = 5–10 per group). The general condition of mice was monitored daily until experiment ended. Kaplan-Meier survival curves were plotted. P-value was assessed with Mantel-Cox tests compared to mice xenografted with Nalm6control. (C) Inhibition curves from Nalm6control, Nalm6+RUNX1, Nalm6+FUBP1, and Nalm6+RUNX1+FUBP1 cell lines treated with 100 ng/ml of SCF and with growing concentrations of imatinib mesylate (0–10 μM) for 48h. Each point is the mean of four biological replicates ± S.E.M. Statistical significance was assessed at 10 μM compared to Nalm6control by Mann–Whitney tests (*P < 0.05).

References

    1. Sood R., Kamikubo Y., Liu P.. Role of RUNX1 in hematological malignancies. Blood. 2017; 129:2070–2082.
    1. Yzaguirre A.D., de Bruijn M.F.T.R., Speck N.A.. The role of Runx1 in embryonic blood cell formation. Adv. Exp. Med. Biol. 2017; 962:47–64.
    1. Brady G., Elgueta Karstegl C., Farrell P.J.. Novel function of the unique N-terminal region of RUNX1c in B cell growth regulation. Nucleic Acids Res. 2013; 41:1555–1568.
    1. Hayashi K., Natsume W., Watanabe T., Abe N., Iwai N., Okada H., Ito Y., Asano M., Iwakura Y., Habu S. et al. . Diminution of the AML1 transcription factor function causes differential effects on the fates of CD4 and CD8 single-positive T cells. J. Immunol. 2000; 165:6816–6824.
    1. Huang G., Zhang P., Hirai H., Elf S., Yan X., Chen Z., Koschmieder S., Okuno Y., Dayaram T., Growney J.D. et al. . PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis. Nat. Genet. 2008; 40:51–60.
    1. Ichikawa M., Asai T., Chiba S., Kurokawa M., Ogawa S.. Runx1/AML-1 ranks as a master regulator of adult hematopoiesis. Cell Cycle. 2004; 3:722–724.
    1. Ichikawa M., Yoshimi A., Nakagawa M., Nishimoto N., Watanabe-Okochi N., Kurokawa M.. A role for RUNX1 in hematopoiesis and myeloid leukemia. Int. J. Hematol. 2013; 97:726–734.
    1. Lorsbach R.B., Moore J., Ang S.O., Sun W., Lenny N., Downing J.R.. Role of RUNX1 in adult hematopoiesis: analysis of RUNX1-IRES-GFP knock-in mice reveals differential lineage expression. Blood. 2004; 103:2522–2529.
    1. Okuda T., van Deursen J., Hiebert S.W., Grosveld G., Downing J.R.. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell. 1996; 84:321–330.
    1. Wang Q., Stacy T., Binder M., Marin-Padilla M., Sharpe A.H., Speck N.A.. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl. Acad. Sci. U.S.A. 1996; 93:3444–3449.
    1. Bonifer C., Levantini E., Kouskoff V., Lacaud G.. Runx1 structure and function in blood cell development. Adv. Exp. Med. Biol. 2017; 962:65–81.
    1. Ito Y., Bae S.-C., Chuang L.S.H.. The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer. 2015; 15:81–95.
    1. Huang G., Shigesada K., Ito K., Wee H.-J., Yokomizo T., Ito Y.. Dimerization with PEBP2β protects RUNX1/AML1 from ubiquitin–proteasome-mediated degradation. EMBO J. 2001; 20:723–733.
    1. Wang Q., Stacy T., Miller J.D., Lewis A.F., Gu T.L., Huang X., Bushweller J.H., Bories J.C., Alt F.W., Ryan G. et al. . The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell. 1996; 87:697–708.
    1. Draper J.E., Sroczynska P., Tsoulaki O., Leong H.S., Fadlullah M.Z.H., Miller C., Kouskoff V., Lacaud G.. RUNX1B Expression is highly heterogeneous and distinguishes megakaryocytic and erythroid lineage fate in adult mouse hematopoiesis. PLoS Genet. 2016; 12:e1005814.
    1. Niebuhr B., Kriebitzsch N., Fischer M., Behrens K., Gunther T., Alawi M., Bergholz U., Muller U., Roscher S., Ziegler M. et al. . Runx1 is essential at two stages of early murine B-cell development. Blood. 2013; 122:413–423.
    1. Davis-Smyth T., Duncan R.C., Zheng T., Michelotti G., Levens D.. The far upstream element-binding proteins comprise an ancient family of single-strand DNA-binding transactivators. J. Biol. Chem. 1996; 271:31679–31687.
    1. Duncan R., Bazar L., Michelotti G., Tomonaga T., Krutzsch H., Avigan M., Levens D.. A sequence-specific, single-strand binding protein activates the far upstream element of c-myc and defines a new DNA-binding motif. Genes Dev. 1994; 8:465–480.
    1. Zhang J., Chen Q.M.. Far upstream element binding protein 1: a commander of transcription, translation and beyond. Oncogene. 2013; 32:2907–2916.
    1. Avigan M.I., Strober B., Levens D.. A far upstream element stimulates c-myc expression in undifferentiated leukemia cells. J. Biol. Chem. 1990; 265:18538–18545.
    1. Malz M., Weber A., Singer S., Riehmer V., Bissinger M., Riener M.-O., Longerich T., Soll C., Vogel A., Angel P. et al. . Overexpression of far upstream element binding proteins: A mechanism regulating proliferation and migration in liver cancer cells. Hepatology. 2009; 50:1130–1139.
    1. Rabenhorst U., Beinoraviciute-Kellner R., Brezniceanu M.-L., Joos S., Devens F., Lichter P., Rieker R.J., Trojan J., Chung H.-J., Levens D.L. et al. . Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth. Hepatology. 2009; 50:1121–1129.
    1. Guo L., Zaysteva O., Nie Z., Mitchell N.C., Amanda Lee J.E., Ware T., Parsons L., Luwor R., Poortinga G., Hannan R.D. et al. . Defining the essential function of FBP/KSRP proteins: Drosophila Psi interacts with the mediator complex to modulate MYC transcription and tissue growth. Nucleic Acids Res. 2016; 44:7646–7658.
    1. Huang P.-N., Lin J.-Y., Locker N., Kung Y.-A., Hung C.-T., Lin J.-Y., Huang H.-I., Li M.-L., Shih S.-R.. Far upstream element binding protein 1 binds the internal ribosomal entry site of enterovirus 71 and enhances viral translation and viral growth. Nucleic Acids Res. 2011; 39:9633–9648.
    1. Irwin N., Baekelandt V., Goritchenko L., Benowitz L.I.. Identification of two proteins that bind to a pyrimidine-rich sequence in the 3′-untranslated region of GAP-43 mRNA. Nucleic Acids Res. 1997; 25:1281–1288.
    1. Lin J.-Y., Li M.-L., Shih S.-R.. Far upstream element binding protein 2 interacts with enterovirus 71 internal ribosomal entry site and negatively regulates viral translation. Nucleic Acids Res. 2009; 37:47–59.
    1. Miro J., Laaref A.M., Rofidal V., Lagrafeuille R., Hem S., Thorel D., Mechin D., Mamchaoui K., Mouly V., Claustres M. et al. . FUBP1: a new protagonist in splicing regulation of the DMD gene. Nucleic Acids Res. 2015; 43:2378–2389.
    1. Bettegowda C., Agrawal N., Jiao Y., Sausen M., Wood L.D., Hruban R.H., Rodriguez F.J., Cahill D.P., McLendon R., Riggins G. et al. . Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011; 333:1453–1455.
    1. Singer S., Malz M., Herpel E., Warth A., Bissinger M., Keith M., Muley T., Meister M., Hoffmann H., Penzel R. et al. . Coordinated expression of stathmin family members by far upstream sequence Element-Binding Protein-1 increases motility in Non–Small cell lung cancer. Cancer Res. 2009; 69:2234–2243.
    1. Weber A., Kristiansen I., Johannsen M., Oelrich B., Scholmann K., Gunia S., May M., Meyer H.-A., Behnke S., Moch H. et al. . The FUSE binding proteins FBP1 and FBP3 are potential c-myc regulators in renal, but not in prostate and bladder cancer. BMC Cancer. 2008; 8:369.
    1. Yang L., Zhu J., Zhang J., Bao B., Guan C., Yang X., Liu Y., Huang Y., Ni R., Ji L.. Far upstream element-binding protein 1 (FUBP1) is a potential c-Myc regulator in esophageal squamous cell carcinoma (ESCC) and its expression promotes ESCC progression. Tumor Biol. 2016; 37:4115–4126.
    1. Rabenhorst U., Thalheimer F.B., Gerlach K., Kijonka M., Böhm S., Krause D.S., Vauti F., Arnold H.-H., Schroeder T., Schnütgen F. et al. . Single-Stranded DNA-Binding transcriptional regulator FUBP1 is essential for fetal and adult hematopoietic stem cell Self-Renewal. Cell Rep. 2015; 11:1847–1855.
    1. Zhou W., Chung Y.-J., Parrilla Castellar E.R., Zheng Y., Chung H.-J., Bandle R., Liu J., Tessarollo L., Batchelor E., Aplan P.D. et al. . Far upstream element binding protein plays a crucial role in embryonic development, hematopoiesis, and stabilizing Myc expression levels. Am. J. Pathol. 2016; 186:701–715.
    1. Klener P., Fronkova E., Berkova A., Jaksa R., Lhotska H., Forsterova K., Soukup J., Kulvait V., Vargova J., Fiser K. et al. . Mantle cell lymphoma-variant Richter syndrome: Detailed molecular-cytogenetic and backtracking analysis reveals slow evolution of a pre-MCL clone in parallel with CLL over several years: Mantle cell lymphoma-variant Richter syndrome. Int. J. Cancer. 2016; 139:2252–2260.
    1. Lindqvist C.M., Lundmark A., Nordlund J., Freyhult E., Ekman D., Almlöf J.C., Raine A., Övernäs E., Abrahamsson J., Frost B.-M. et al. . Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. Oncotarget. 2016; 7:64071–64088.
    1. Landau D.A., Tausch E., Taylor-Weiner A.N., Stewart C., Reiter J.G., Bahlo J., Kluth S., Bozic I., Lawrence M., Böttcher S. et al. . Mutations driving CLL and their evolution in progression and relapse. Nature. 2015; 526:525–530.
    1. Ashman L.K. The biology of stem cell factor and its receptor C-kit. Int. J. Biochem. Cell Biol. 1999; 31:1037–1051.
    1. Broudy V.C. Stem cell factor and hematopoiesis. Blood. 1997; 90:1345–1364.
    1. Miettinen M., Lasota J.. KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl. Immunohistochem. Mol. Morphol. 2005; 13:205–220.
    1. Yarden Y., Kuang W.J., Yang-Feng T., Coussens L., Munemitsu S., Dull T.J., Chen E., Schlessinger J., Francke U., Ullrich A.. Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J. 1987; 6:3341–3351.
    1. Mohammed H., D’Santos C., Serandour A.A., Ali H.R., Brown G.D., Atkins A., Rueda O.M., Holmes K.A., Theodorou V., Robinson J.L.L. et al. . Endogenous purification reveals GREB1 as a key estrogen receptor regulatory factor. Cell Rep. 2013; 3:342–349.
    1. Debaize L., Jakobczyk H., Rio A.-G., Gandemer V., Troadec M.-B.. Optimization of proximity ligation assay (PLA) for detection of protein interactions and fusion proteins in non-adherent cells: application to pre-B lymphocytes. Mol. Cytogenet. 2017; 10:27.
    1. Stewart S.A., Dykxhoorn D.M., Palliser D., Mizuno H., Yu E.Y., An D.S., Sabatini D.M., Chen I.S.Y., Hahn W.C., Sharp P.A. et al. . Lentivirus-delivered stable gene silencing by RNAi in primary cells. RNA. 2003; 9:493–501.
    1. Arnaud M.-P., Vallée A., Robert G., Bonneau J., Leroy C., Varin-Blank N., Rio A.-G., Troadec M.-B., Galibert M.-D., Gandemer V.. CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling. Blood. 2015; 126:1802–1812.
    1. Campeau E., Ruhl V.E., Rodier F., Smith C.L., Rahmberg B.L., Fuss J.O., Campisi J., Yaswen P., Cooper P.K., Kaufman P.D.. A versatile viral system for expression and depletion of proteins in mammalian cells. PLoS ONE. 2009; 4:e6529.
    1. Sérandour A.A., Avner S., Oger F., Bizot M., Percevault F., Lucchetti-Miganeh C., Palierne G., Gheeraert C., Barloy-Hubler F., Péron C.L. et al. . Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers. Nucleic Acids Res. 2012; 40:8255–8265.
    1. Shin H., Liu T., Manrai A.K., Liu X.S.. CEAS: cis-regulatory element annotation system. Bioinforma. Oxf. Engl. 2009; 25:2605–2606.
    1. McLean C.Y., Bristor D., Hiller M., Clarke S.L., Schaar B.T., Lowe C.B., Wenger A.M., Bejerano G.. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 2010; 28:495–501.
    1. Nègre D., Mangeot P.E., Duisit G., Blanchard S., Vidalain P.O., Leissner P., Winter A.J., Rabourdin-Combe C., Mehtali M., Moullier P. et al. . Characterization of novel safe lentiviral vectors derived from simian immunodeficiency virus (SIVmac251) that efficiently transduce mature human dendritic cells. Gene Ther. 2000; 7:1613–1623.
    1. Zheng Y., Miskimins W.K.. Far upstream element binding protein 1 activates translation of p27Kip1 mRNA through its internal ribosomal entry site. Int. J. Biochem. Cell Biol. 2011; 43:1641–1648.
    1. Krieger E., Vriend G.. New ways to boost molecular dynamics simulations. J. Comput. Chem. 2015; 36:996–1007.
    1. He L., Weber A., Levens D.. Nuclear targeting determinants of the far upstream element binding protein, a c-myc transcription factor. Nucleic Acids Res. 2000; 28:4558–4565.
    1. Lu J., Maruyama M., Satake M., Bae S.C., Ogawa E., Kagoshima H., Shigesada K., Ito Y.. Subcellular localization of the alpha and beta subunits of the acute myeloid leukemia-linked transcription factor PEBP2/CBF. Mol. Cell. Biol. 1995; 15:1651–1661.
    1. Zelent A., Greaves M., Enver T.. Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene. 2004; 23:4275–4283.
    1. Melchers F. Checkpoints that control B cell development. J. Clin. Invest. 2015; 125:2203–2210.
    1. Atanassov B.S., Dent S.Y.R.. USP22 regulates cell proliferation by deubiquitinating the transcriptional regulator FBP1. EMBO Rep. 2011; 12:924–930.
    1. Rabenhorst U., Beinoraviciute-Kellner R., Brezniceanu M.-L., Joos S., Devens F., Lichter P., Rieker R.J., Trojan J., Chung H.-J., Levens D.L. et al. . Overexpression of the far upstream element binding protein 1 in hepatocellular carcinoma is required for tumor growth. Hepatol. Baltim. Md. 2009; 50:1121–1129.
    1. Malz M., Bovet M., Samarin J., Rabenhorst U., Sticht C., Bissinger M., Roessler S., Bermejo J.L., Renner M., Calvisi D.F. et al. . Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma. Hepatology. 2014; 60:1241–1250.
    1. Braddock D.T., Louis J.M., Baber J.L., Levens D., Clore G.M.. Structure and dynamics of KH domains from FBP bound to single-stranded DNA. Nature. 2002; 415:1051–1056.
    1. Levanon D., Groner Y.. Structure and regulated expression of mammalian RUNX genes. Oncogene. 2004; 23:4211–4219.
    1. Sandelin A., Alkema W., Engström P., Wasserman W.W., Lenhard B.. JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res. 2004; 32:D91–D94.
    1. Matheny C.J., Speck M.E., Cushing P.R., Zhou Y., Corpora T., Regan M., Newman M., Roudaia L., Speck C.L., Gu T.-L. et al. . Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles. EMBO J. 2007; 26:1163–1175.
    1. Zhang L., Li Z., Yan J., Pradhan P., Corpora T., Cheney M.D., Bravo J., Warren A.J., Bushweller J.H., Speck N.A.. Mutagenesis of the Runt domain defines two energetic hot spots for heterodimerization with the core binding factor beta subunit. J. Biol. Chem. 2003; 278:33097–33104.
    1. Benjamin L.R., Chung H.-J., Sanford S., Kouzine F., Liu J., Levens D.. Hierarchical mechanisms build the DNA-binding specificity of FUSE binding protein. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:18296–18301.
    1. Siomi H., Matunis M.J., Michael W.M., Dreyfuss G.. The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res. 1993; 21:1193–1198.
    1. Sully G., Dean J.L.E., Wait R., Rawlinson L., Santalucia T., Saklatvala J., Clark A.R.. Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochem. J. 2004; 377:629–639.
    1. Zhou X., Edmonson M.N., Wilkinson M.R., Patel A., Wu G., Liu Y., Li Y., Zhang Z., Rusch M.C., Parker M. et al. . Exploring genomic alteration in pediatric cancer using ProteinPaint. Nat. Genet. 2016; 48:4–6.
    1. Lennartsson J., Jelacic T., Linnekin D., Shivakrupa R.. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005; 23:16–43.
    1. Yee N.S., Hsiau C.W., Serve H., Vosseller K., Besmer P.. Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3′-kinase, and protein kinase C. J. Biol. Chem. 1994; 269:31991–31998.
    1. He L., Liu J., Collins I., Sanford S., O’Connell B., Benham C.J., Levens D.. Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression. EMBO J. 2000; 19:1034–1044.
    1. Cammenga J., Horn S., Bergholz U., Sommer G., Besmer P., Fiedler W., Stocking C.. Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood. 2005; 106:3958–3961.
    1. Tian Y., Wang G., Hu Q., Xiao X., Chen S.. AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer. J. Cell. Biochem. 2017; 119:3706–3715.
    1. Liu J., He L., Collins I., Ge H., Libutti D., Li J., Egly J.-M., Levens D.. The FBP interacting repressor targets TFIIH to inhibit activated transcription. Mol. Cell. 2000; 5:331–341.
    1. Liu J., Chung H.-J., Vogt M., Jin Y., Malide D., He L., Dundr M., Levens D.. JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J. 2011; 30:846–858.
    1. Sykora K.W., Tomeczkowski J., Reiter A.. C-Kit receptors in childhood malignant lymphoblastic cells. Leuk. Lymphoma. 1997; 25:201–216.
    1. Andersson A., Olofsson T., Lindgren D., Nilsson B., Ritz C., Edén P., Lassen C., Råde J., Fontes M., Mörse H. et al. . Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. Proc. Natl. Acad. Sci. U.S.A. 2005; 102:19069–19074.
    1. Ikeda H., Kanakura Y., Tamaki T., Kuriu A., Kitayama H., Ishikawa J., Kanayama Y., Yonezawa T., Tarui S., Griffin J.D.. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood. 1991; 78:2962–2968.
    1. Weidemann R.R., Behrendt R., Schoedel K.B., Müller W., Roers A., Gerbaulet A.. Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice. Exp. Hematol. 2017; 45:45–55.
    1. Eppert K., Takenaka K., Lechman E.R., Waldron L., Nilsson B., van Galen P., Metzeler K.H., Poeppl A., Ling V., Beyene J. et al. . Stem cell gene expression programs influence clinical outcome in human leukemia. Nat. Med. 2011; 17:1086–1093.
    1. Gandemer V., Rio A.G., de Tayrac M., Sibut V., Mottier S., Ly Sunnaram B., Henry C., Monnier A., Berthou C., Le Gall E. et al. . Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia. BMC Genomics. 2007; 8:385.
    1. Jiao X., Sherman B.T., Huang D.W., Stephens R., Baseler M.W., Lane H.C., Lempicki R.A.. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 2012; 28:1805–1806.
    1. Nicol J.W., Helt G.A., Blanchard S.G., Raja A., Loraine A.E.. The integrated genome Browser: free software for distribution and exploration of genome-scale datasets. Bioinforma. Oxf. Engl. 2009; 25:2730–2731.
    1. Chenna R., Sugawara H., Koike T., Lopez R., Gibson T.J., Higgins D.G., Thompson J.D.. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Res. 2003; 31:3497–3500.
    1. Efremov R.G., Chugunov A.O., Pyrkov T.V., Priestle J.P., Arseniev A.S., Jacoby E.. Molecular lipophilicity in protein modeling and drug design. Curr. Med. Chem. 2007; 14:393–415.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere