Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

RUNX1 Dosage in Development and Cancer

  • Lie-a-ling, Michael (Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester) ;
  • Mevel, Renaud (Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester) ;
  • Patel, Rahima (Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester) ;
  • Blyth, Karen (Cancer Research UK Beatson Institute) ;
  • Baena, Esther (Cancer Research UK Prostate Oncobiology Group, Cancer Research UK Manchester Institute, The University of Manchester) ;
  • Kouskoff, Valerie (Division of Developmental Biology & Medicine, The University of Manchester) ;
  • Lacaud, Georges (Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester)
  • Received : 2019.12.02
  • Accepted : 2019.12.04
  • Published : 2020.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

The transcription factor RUNX1 first came to prominence due to its involvement in the t(8;21) translocation in acute myeloid leukemia (AML). Since this discovery, RUNX1 has been shown to play important roles not only in leukemia but also in the ontogeny of the normal hematopoietic system. Although it is currently still challenging to fully assess the different parameters regulating RUNX1 dosage, it has become clear that the dose of RUNX1 can greatly affect both leukemia and normal hematopoietic development. It is also becoming evident that varying levels of RUNX1 expression can be used as markers of tumor progression not only in the hematopoietic system, but also in non-hematopoietic cancers. Here, we provide an overview of the current knowledge of the effects of RUNX1 dosage in normal development of both hematopoietic and epithelial tissues and their associated cancers.

Keywords

References

  1. Aikawa, Y., Nguyen, L.A., Isono, K., Takakura, N., Tagata, Y., Schmitz, M.L., Koseki, H., and Kitabayashi, I. (2006). Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. EMBO J. 25, 3955-3965. https://doi.org/10.1038/sj.emboj.7601273
  2. Angelos, M.G., Abrahante, J.E., Blum, R.H., and Kaufman, D.S. (2018). Single cell resolution of human hematoendothelial cells defines transcriptional signatures of hemogenic endothelium. Stem Cells 36, 206-217. https://doi.org/10.1002/stem.2739
  3. Aronson, B.D., Fisher, A.L., Blechman, K., Caudy, M., and Gergen, J.P. (1997). Groucho-dependent and -independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17, 5581-5587. https://doi.org/10.1128/MCB.17.9.5581
  4. Bae, S.C., Yamaguchi-Iwai, Y., Ogawa, E., Maruyama, M., Inuzuka, M., Kagoshima, H., Shigesada, K., Satake, M., and Ito, Y. (1993). Isolation of PEBP2 alpha B cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1. Oncogene 8, 809-814.
  5. Banach-Petrosky, W., Jessen, W.J., Ouyang, X., Gao, H., Rao, J., Quinn, J., Aronow, B.J., and Abate-Shen, C. (2007). Prolonged exposure to reduced levels of androgen accelerates prostate cancer progression in Nkx3.1; Pten mutant mice. Cancer Res. 67, 9089-9096. https://doi.org/10.1158/0008-5472.CAN-07-2887
  6. Banerji, S., Cibulskis, K., Rangel-Escareno, C., Brown, K.K., Carter, S.L., Frederick, A.M., Lawrence, M.S., Sivachenko, A.Y., Sougnez, C., Zou, L., et al. (2012). Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405-409. https://doi.org/10.1038/nature11154
  7. Baron, C.S., Kester, L., Klaus, A., Boisset, J.C., Thambyrajah, R., Yvernogeau, L., Kouskoff, V., Lacaud, G., van Oudenaarden, A., and Robin, C. (2018). Single-cell transcriptomics reveal the dynamic of haematopoietic stem cell production in the aorta. Nat. Commun. 9, 2517. https://doi.org/10.1038/s41467-018-04893-3
  8. Batcha, A.M.N., Bamopoulos, S.A., Kerbs, P., Kumar, A., Jurinovic, V., Rothenberg-Thurley, M., Ksienzyk, B., Philippou-Massier, J., Krebs, S., Blum, H., et al. (2019). Allelic imbalance of recurrently mutated genes in acute myeloid leukaemia. Sci. Rep. 9, 11796. https://doi.org/10.1038/s41598-019-48167-4
  9. Bee, T., Liddiard, K., Swiers, G., Bickley, S.R., Vink, C.S., Jarratt, A., Hughes, J.R., Medvinsky, A., and de Bruijn, M.F. (2009). Alternative Runx1 promoter usage in mouse developmental hematopoiesis. Blood Cells Mol. Dis. 43, 35-42. https://doi.org/10.1016/j.bcmd.2009.03.011
  10. Bee, T., Swiers, G., Muroi, S., Pozner, A., Nottingham, W., Santos, A.C., Li, P.S., Taniuchi, I., and de Bruijn, M.F. (2010). Nonredundant roles for Runx1 alternative promoters reflect their activity at discrete stages of developmental hematopoiesis. Blood 115, 3042-3050. https://doi.org/10.1182/blood-2009-08-238626
  11. Behrens, K., Maul, K., Tekin, N., Kriebitzsch, N., Indenbirken, D., Prassolov, V., Muller, U., Serve, H., Cammenga, J., and Stocking, C. (2017). RUNX1 cooperates with FLT3-ITD to induce leukemia. J. Exp. Med. 214, 737-752. https://doi.org/10.1084/jem.20160927
  12. Bellissimo, D.C. and Speck, N.A. (2017). RUNX1 mutations in inherited and sporadic leukemia. Front. Cell Dev. Biol. 5, 111. https://doi.org/10.3389/fcell.2017.00111
  13. Beltran, H., Prandi, D., Mosquera, J.M., Benelli, M., Puca, L., Cyrta, J., Marotz, C., Giannopoulou, E., Chakravarthi, B.V., Varambally, S., et al. (2016). Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298-305. https://doi.org/10.1038/nm.4045
  14. Ben-Ami, O., Friedman, D., Leshkowitz, D., Goldenberg, D., Orlovsky, K., Pencovich, N., Lotem, J., Tanay, A., and Groner, Y. (2013). Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. Cell Rep. 4, 1131-1143. https://doi.org/10.1016/j.celrep.2013.08.020
  15. Biggs, J.R., Peterson, L.F., Zhang, Y., Kraft, A.S., and Zhang, D.E. (2006). AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol. Cell. Biol. 26, 7420-7429. https://doi.org/10.1128/MCB.00597-06
  16. Blumenthal, E., Greenblatt, S., Huang, G., Ando, K., Xu, Y., and Nimer, S.D. (2017). Covalent modifications of RUNX proteins: structure affects function. Adv. Exp. Med. Biol. 962, 33-44. https://doi.org/10.1007/978-981-10-3233-2_3
  17. Blyth, K., Cameron, E.R., and Neil, J.C. (2005). The RUNX genes: gain or loss of function in cancer. Nat. Rev. Cancer 5, 376-387. https://doi.org/10.1038/nrc1607
  18. Blyth, K., Vaillant, F., Jenkins, A., McDonald, L., Pringle, M.A., Huser, C., Stein, T., Neil, J., and Cameron, E.R. (2010). Runx2 in normal tissues and cancer cells: a developing story. Blood Cells Mol. Dis. 45, 117-123. https://doi.org/10.1016/j.bcmd.2010.05.007
  19. Boisset, J.C., van Cappellen, W., Andrieu-Soler, C., Galjart, N., Dzierzak, E., and Robin, C. (2010). In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature 464, 116-120. https://doi.org/10.1038/nature08764
  20. Bravo, J., Li, Z., Speck, N.A., and Warren, A.J. (2001). The leukemiaassociated AML1 (Runx1)--CBF beta complex functions as a DNA-induced molecular clamp. Nat. Struct. Biol. 8, 371-378. https://doi.org/10.1038/86264
  21. Browne, G., Taipaleenmaki, H., Bishop, N.M., Madasu, S.C., Shaw, L.M., van Wijnen, A.J., Stein, J.L., Stein, G.S., and Lian, J.B. (2015). Runx1 is associated with breast cancer progression in MMTV-PyMT transgenic mice and its depletion in vitro inhibits migration and invasion. J. Cell. Physiol. 230, 2522-2532. https://doi.org/10.1002/jcp.24989
  22. Bruno, L., Ramlall, V., Studer, R.A., Sauer, S., Bradley, D., Dharmalingam, G., Carroll, T., Ghoneim, M., Chopin, M., Nutt, S.L., et al. (2019). Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system. Nat. Immunol. 20, 1372-1380. https://doi.org/10.1038/s41590-019-0471-5
  23. Cai, Z., de Bruijn, M., Ma, X., Dortland, B., Luteijn, T., Downing, R.J., and Dzierzak, E. (2000). Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo. Immunity 13, 423-431. https://doi.org/10.1016/S1074-7613(00)00042-X
  24. Cancer Genome Atlas Network (2012). Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70. https://doi.org/10.1038/nature11412
  25. Challen, G.A. and Goodell, M.A. (2010). Runx1 isoforms show differential expression patterns during hematopoietic development but have similar functional effects in adult hematopoietic stem cells. Exp. Hematol. 38, 403-416. https://doi.org/10.1016/j.exphem.2010.02.011
  26. Chen, B., Teng, J., Liu, H., Pan, X., Zhou, Y., Huang, S., Lai, M., Bian, G., Mao, B., Sun, W., et al. (2017). Inducible overexpression of RUNX1b/c in human embryonic stem cells blocks early hematopoiesis from mesoderm. J. Mol. Cell Biol. 9, 262-273. https://doi.org/10.1093/jmcb/mjx032
  27. Chen, M.J., Yokomizo, T., Zeigler, B.M., Dzierzak, E., and Speck, N.A. (2009). Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887-891. https://doi.org/10.1038/nature07619
  28. Chimge, N.O., Little, G.H., Baniwal, S.K., Adisetiyo, H., Xie, Y., Zhang, T., O'Laughlin, A., Liu, Z.Y., Ulrich, P., Martin, A., et al. (2016). RUNX1 prevents oestrogen-mediated AXIN1 suppression and beta-catenin activation in ER-positive breast cancer. Nat. Commun. 7, 10751. https://doi.org/10.1038/ncomms10751
  29. Choi, A., Illendula, A., Pulikkan, J.A., Roderick, J.E., Tesell, J., Yu, J., Hermance, N., Zhu, L.J., Castilla, L.H., Bushweller, J.H., et al. (2017). RUNX1 is required for oncogenic Myb and Myc enhancer activity in T-cell acute lymphoblastic leukemia. Blood 130, 1722-1733. https://doi.org/10.1182/blood-2017-03-775536
  30. Chuang, L.S., Ito, K., and Ito, Y. (2013). RUNX family: regulation and diversification of roles through interacting proteins. Int. J. Cancer 132, 1260-1271. https://doi.org/10.1002/ijc.27964
  31. Ditadi, A., Sturgeon, C.M., Tober, J., Awong, G., Kennedy, M., Yzaguirre, A.D., Azzola, L., Ng, E.S., Stanley, E.G., French, D.L., et al. (2015). Human definitive haemogenic endothelium and arterial vascular endothelium represent distinct lineages. Nat. Cell Biol. 17, 580-591. https://doi.org/10.1038/ncb3161
  32. Doll, A., Gonzalez, M., Abal, M., Llaurado, M., Rigau, M., Colas, E., Monge, M., Xercavins, J., Capella, G., Diaz, B., et al. (2009). An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis. Int. J. Cancer 125, 257-263. https://doi.org/10.1002/ijc.24330
  33. Draper, J.E., Sroczynska, P., Tsoulaki, O., Leong, H.S., Fadlullah, M.Z., Miller, C., Kouskoff, V., and Lacaud, G. (2016). RUNX1B expression is highly heterogeneous and distinguishes megakaryocytic and erythroid lineage fate in adult mouse hematopoiesis. PLoS Genet 12, e1005814. https://doi.org/10.1371/journal.pgen.1005814
  34. Dzierzak, E. and Bigas, A. (2018). Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell 22, 639-651. https://doi.org/10.1016/j.stem.2018.04.015
  35. Eilken, H.M., Nishikawa, S., and Schroeder, T. (2009). Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature 457, 896-900. https://doi.org/10.1038/nature07760
  36. Ellis, M.J., Ding, L., Shen, D., Luo, J., Suman, V.J., Wallis, J.W., Van Tine, B.A., Hoog, J., Goiffon, R.J., Goldstein, T.C., et al. (2012). Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353-360. https://doi.org/10.1038/nature11143
  37. Ferrari, N., Mohammed, Z.M., Nixon, C., Mason, S.M., Mallon, E., McMillan, D.C., Morris, J.S., Cameron, E.R., Edwards, J., and Blyth, K. (2014). Expression of RUNX1 correlates with poor patient prognosis in triple negative breast cancer. PLoS One 9, e100759. https://doi.org/10.1371/journal.pone.0100759
  38. Fijneman, R.J., Anderson, R.A., Richards, E., Liu, J., Tijssen, M., Meijer, G.A., Anderson, J., Rod, A., O'Sullivan, M.G., Scott, P.M., et al. (2012). Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci. 103, 593-599. https://doi.org/10.1111/j.1349-7006.2011.02189.x
  39. Fu, Y., Sun, S., Man, X., and Kong, C. (2019). Increased expression of RUNX1 in clear cell renal cell carcinoma predicts poor prognosis. PeerJ 7, e7854. https://doi.org/10.7717/peerj.7854
  40. 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. (2007). Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia. BMC Genomics 8, 385. https://doi.org/10.1186/1471-2164-8-385
  41. Ghozi, M.C., Bernstein, Y., Negreanu, V., Levanon, D., and Groner, Y. (1996). Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions. Proc. Natl. Acad. Sci. U. S. A. 93, 1935-1940. https://doi.org/10.1073/pnas.93.5.1935
  42. Goode, D.K., Obier, N., Vijayabaskar, M.S., Lie, A.L.M., Lilly, A.J., Hannah, R., Lichtinger, M., Batta, K., Florkowska, M., Patel, R., et al. (2016). Dynamic gene regulatory networks drive hematopoietic specification and differentiation. Dev. Cell 36, 572-587. https://doi.org/10.1016/j.devcel.2016.01.024
  43. Goyama, S., Huang, G., Kurokawa, M., and Mulloy, J.C. (2015). Posttranslational modifications of RUNX1 as potential anticancer targets. Oncogene 34, 3483-3492. https://doi.org/10.1038/onc.2014.305
  44. Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., Nakagawa, M., Olsson, A., Wunderlich, M., Link, K.A., et al. (2013). Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J. Clin. Invest. 123, 3876-3888. https://doi.org/10.1172/JCI68557
  45. Goyama, S., Yamaguchi, Y., Imai, Y., Kawazu, M., Nakagawa, M., Asai, T., Kumano, K., Mitani, K., Ogawa, S., Chiba, S., et al. (2004). The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region. Blood 104, 3558-3564.
  46. Guo, H. and Friedman, A.D. (2011). Phosphorylation of RUNX1 by cyclindependent kinase reduces direct interaction with HDAC1 and HDAC3. J. Biol. Chem. 286, 208-215. https://doi.org/10.1074/jbc.M110.149013
  47. Hamidi, S. and Sheng, G. (2018). Epithelial-mesenchymal transition in haematopoietic stem cell development and homeostasis. J. Biochem. 164, 265-275. https://doi.org/10.1093/jb/mvy063
  48. Hoi, C.S., Lee, S.E., Lu, S.Y., McDermitt, D.J., Osorio, K.M., Piskun, C.M., Peters, R.M., Paus, R., and Tumbar, T. (2010). Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol. Cell. Biol. 30, 2518-2536. https://doi.org/10.1128/MCB.01308-09
  49. Hong, D., Fritz, A.J., Gordon, J.A., Tye, C.E., Boyd, J.R., Tracy, K.M., Frietze, S.E., Carr, F.E., Nickerson, J.A., Van Wijnen, A.J., et al. (2019). RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J. Cell. Physiol. 234, 8597-8609. https://doi.org/10.1002/jcp.27841
  50. Hong, D., Messier, T.L., Tye, C.E., Dobson, J.R., Fritz, A.J., Sikora, K.R., Browne, G., Stein, J.L., Lian, J.B., and Stein, G.S. (2017). Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition. Oncotarget 8, 17610-17627. https://doi.org/10.18632/oncotarget.15381
  51. Huang, G., Shigesada, K., Ito, K., Wee, H.J., Yokomizo, T., and Ito, Y. (2001). Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitinproteasome-mediated degradation. EMBO J. 20, 723-733. https://doi.org/10.1093/emboj/20.4.723
  52. Huang, H., Woo, A.J., Waldon, Z., Schindler, Y., Moran, T.B., Zhu, H.H., Feng, G.S., Steen, H., and Cantor, A.B. (2012). A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev. 26, 1587-1601. https://doi.org/10.1101/gad.192054.112
  53. Huang, S.P., Lan, Y.H., Lu, T.L., Pao, J.B., Chang, T.Y., Lee, H.Z., Yang, W.H., Hsieh, C.J., Chen, L.M., Huang, L.C., et al. (2011). Clinical significance of runt-related transcription factor 1 polymorphism in prostate cancer. BJU Int. 107, 486-492. https://doi.org/10.1111/j.1464-410X.2010.09512.x
  54. Hyde, R.K., Zhao, L., Alemu, L., and Liu, P. P. (2015). Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice. Leukemia 29, 1771-1778. https://doi.org/10.1038/leu.2015.58
  55. Imai, Y., Kurokawa, M., Yamaguchi, Y., Izutsu, K., Nitta, E., Mitani, K., Satake, M., Noda, T., Ito, Y., and Hirai, H. (2004). The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1. Mol. Cell. Biol. 24, 1033-1043. https://doi.org/10.1128/MCB.24.3.1033-1043.2004
  56. Islam, R., Yoon, W.J., Woo, K.M., Baek, J.H., and Ryoo, H.M. (2014). Pin1- mediated prolyl isomerization of Runx1 affects PU.1 expression in premonocytes. J. Cell. Physiol. 229, 443-452. https://doi.org/10.1002/jcp.24462
  57. Ito, Y., Bae, S.C., and Chuang, L.S. (2015). The RUNX family: developmental regulators in cancer. Nat. Rev. Cancer 15, 81-95. https://doi.org/10.1038/nrc3877
  58. Jain, P., Nattakom, M., Holowka, D., Wang, D.H., Thomas Brenna, J., Ku, A.T., Nguyen, H., Ibrahim, S.F., and Tumbar, T. (2018). Runx1 role in epithelial and cancer cell proliferation implicates lipid metabolism and Scd1 and Soat1 activity. Stem Cells 36, 1603-1616. https://doi.org/10.1002/stem.2868
  59. Jiang, Q., Qin, X., Kawane, T., Komori, H., Matsuo, Y., Taniuchi, I., Ito, K., Izumi, S., and Komori, T. (2016). Cbfb2 isoform dominates more potent Cbfb1 and is required for skeletal development. J. Bone Miner. Res. 31, 1391-1404. https://doi.org/10.1002/jbmr.2814
  60. Kadota, M., Yang, H.H., Gomez, B., Sato, M., Clifford, R.J., Meerzaman, D., Dunn, B.K., Wakefield, L.M., and Lee, M.P. (2010). Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One 5, e9201. https://doi.org/10.1371/journal.pone.0009201
  61. Kamikubo, Y., Zhao, L., Wunderlich, M., Corpora, T., Hyde, R.K., Paul, T.A., Kundu, M., Garrett, L., Compton, S., Huang, G., et al. (2010). Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Cancer Cell 17, 455-468. https://doi.org/10.1016/j.ccr.2010.03.022
  62. Kanno, T., Kanno, Y., Chen, L.F., Ogawa, E., Kim, W.Y., and Ito, Y. (1998). Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit. Mol. Cell. Biol. 18, 2444-2454. https://doi.org/10.1128/MCB.18.5.2444
  63. Karn, T., Pusztai, L., Holtrich, U., Iwamoto, T., Shiang, C.Y., Schmidt, M., Muller, V., Solbach, C., Gaetje, R., Hanker, L., et al. (2011). Homogeneous datasets of triple negative breast cancers enable the identification of novel prognostic and predictive signatures. PLoS One 6, e28403. https://doi.org/10.1371/journal.pone.0028403
  64. Kas, S.M., de Ruiter, J.R., Schipper, K., Annunziato, S., Schut, E., Klarenbeek, S., Drenth, A.P., van der Burg, E., Klijn, C., Ten Hoeve, J.J., et al. (2017). Insertional mutagenesis identifies drivers of a novel oncogenic pathway in invasive lobular breast carcinoma. Nat. Genet. 49, 1219-1230. https://doi.org/10.1038/ng.3905
  65. Keita, M., Bachvarova, M., Morin, C., Plante, M., Gregoire, J., Renaud, M.C., Sebastianelli, A., Trinh, X.B., and Bachvarov, D. (2013). The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion. Cell Cycle 12, 972-986. https://doi.org/10.4161/cc.23963
  66. Kim, W., Barron, D.A., San Martin, R., Chan, K.S., Tran, L.L., Yang, F., Ressler, S.J., and Rowley, D.R. (2014). RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc. Natl. Acad. Sci. U. S. A. 111, 16389-16394. https://doi.org/10.1073/pnas.1407097111
  67. Komeno, Y., Yan, M., Matsuura, S., Lam, K., Lo, M.C., Huang, Y.J., Tenen, D.G., Downing, J.R., and Zhang, D.E. (2014). Runx1 exon 6-related alternative splicing isoforms differentially regulate hematopoiesis in mice. Blood 123, 3760-3769. https://doi.org/10.1182/blood-2013-08-521252
  68. Kulkarni, M., Tan, T.Z., Syed Sulaiman, N.B., Lamar, J.M., Bansal, P., Cui, J., Qiao, Y., and Ito, Y. (2018). RUNX1 and RUNX3 protect against YAPmediated EMT, stem-ness and shorter survival outcomes in breast cancer. Oncotarget 9, 14175-14192. https://doi.org/10.18632/oncotarget.24419
  69. Lacaud, G., Gore, L., Kennedy, M., Kouskoff, V., Kingsley, P., Hogan, C., Carlsson, L., Speck, N., Palis, J., and Keller, G. (2002). Runx1 is essential for hematopoietic commitment at the hemangioblast stage of development in vitro. Blood 100, 458-466. https://doi.org/10.1182/blood-2001-12-0321
  70. Lacaud, G., Kouskoff, V., Trumble, A., Schwantz, S., and Keller, G. (2004). Haploinsufficiency of Runx1 results in the acceleration of mesodermal development and hemangioblast specification upon in vitro differentiation of ES cells. Blood 103, 886-889. https://doi.org/10.1182/blood-2003-06-2149
  71. Lancrin, C., Sroczynska, P., Stephenson, C., Allen, T., Kouskoff, V., and Lacaud, G. (2009). The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457, 892-895. https://doi.org/10.1038/nature07679
  72. Lee, S.E., Sada, A., Zhang, M., McDermitt, D.J., Lu, S.Y., Kemphues, K.J., and Tumbar, T. (2014). High Runx1 levels promote a reversible, moredifferentiated cell state in hair-follicle stem cells during quiescence. Cell Rep. 6, 499-513. https://doi.org/10.1016/j.celrep.2013.12.039
  73. Leong, W.Y., Guo, H., Ma, O., Huang, H., Cantor, A.B., and Friedman, A.D. (2016). Runx1 phosphorylation by Src increases trans-activation via augmented stability, reduced histone deacetylase (HDAC) binding, and increased DNA affinity, and activated Runx1 favors granulopoiesis. J. Biol. Chem. 291, 826-836. https://doi.org/10.1074/jbc.M115.674234
  74. Levanon, D., Glusman, G., Bangsow, T., Ben-Asher, E., Male, D.A., Avidan, N., Bangsow, C., Hattori, M., Taylor, T.D., Taudien, S., et al. (2001). Architecture and anatomy of the genomic locus encoding the human leukemiaassociated transcription factor RUNX1/AML1. Gene 262, 23-33. https://doi.org/10.1016/S0378-1119(00)00532-1
  75. Levanon, D., Goldstein, R.E., Bernstein, Y., Tang, H., Goldenberg, D., Stifani, S., Paroush, Z., and Groner, Y. (1998). Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl. Acad. Sci. U. S. A. 95, 11590-11595. https://doi.org/10.1073/pnas.95.20.11590
  76. Levanon, D. and Groner, Y. (2004). Structure and regulated expression of mammalian RUNX genes. Oncogene 23, 4211-4219. https://doi.org/10.1038/sj.onc.1207670
  77. Li, Q., Lai, Q., He, C., Fang, Y., Yan, Q., Zhang, Y., Wang, X., Gu, C., Wang, Y., Ye, L., et al. (2019). RUNX1 promotes tumour metastasis by activating the Wnt/beta-catenin signalling pathway and EMT in colorectal cancer. J. Exp. Clin. Cancer Res. 38, 334. https://doi.org/10.1186/s13046-019-1330-9
  78. Liakhovitskaia, A., Gribi, R., Stamateris, E., Villain, G., Jaffredo, T., Wilkie, R., Gilchrist, D., Yang, J., Ure, J., and Medvinsky, A. (2009). Restoration of Runx1 expression in the Tie2 cell compartment rescues definitive hematopoietic stem cells and extends life of Runx1 knockout animals until birth. Stem Cells 27, 1616-1624. https://doi.org/10.1002/stem.71
  79. Lie-A-Ling, M., Marinopoulou, E., Lilly, A.J., Challinor, M., Patel, R., Lancrin, C., Kouskoff, V., and Lacaud, G. (2018). Regulation of RUNX1 dosage is crucial for efficient blood formation from hemogenic endothelium. Development 145, dev149419. https://doi.org/10.1242/dev.149419
  80. Liu, H., Carlsson, L., and Grundstrom, T. (2006). Identification of an N-terminal transactivation domain of Runx1 that separates molecular function from global differentiation function. J. Biol. Chem. 281, 25659-25669. https://doi.org/10.1074/jbc.M603249200
  81. McDonald, L., Ferrari, N., Terry, A., Bell, M., Mohammed, Z.M., Orange, C., Jenkins, A., Muller, W.J., Gusterson, B.A., Neil, J.C., et al. (2014). RUNX2 correlates with subtype-specific breast cancer in a human tissue microarray, and ectopic expression of Runx2 perturbs differentiation in the mouse mammary gland. Dis. Model. Mech. 7, 525-534. https://doi.org/10.1242/dmm.015040
  82. Menegatti, S., de Kruijf, M., Garcia-Alegria, E., Lacaud, G., and Kouskoff, V. (2019). Transcriptional control of blood cell emergence. FEBS Lett. 593, 3304-3315. https://doi.org/10.1002/1873-3468.13585
  83. Mevel, R., Draper, J.E., Lie-A-Ling, M., Kouskoff, V., and Lacaud, G. (2019). RUNX transcription factors: orchestrators of development. Development 146, dev148296. https://doi.org/10.1242/dev.148296
  84. Mill, C.P., Fiskus, W., DiNardo, C.D., Qian, Y., Raina, K., Rajapakshe, K., Perera, D., Coarfa, C., Kadia, T.M., Khoury, J.D., et al. (2019). RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1. Blood 134, 59-73.
  85. Mitsuda, Y., Morita, K., Kashiwazaki, G., Taniguchi, J., Bando, T., Obara, M., Hirata, M., Kataoka, T.R., Muto, M., Kaneda, Y., et al. (2018). RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells. Sci. Rep. 8, 6423. https://doi.org/10.1038/s41598-018-24969-w
  86. Miyagawa, K., Sakakura, C., Nakashima, S., Yoshikawa, T., Kin, S., Nakase, Y., Ito, K., Yamagishi, H., Ida, H., Yazumi, S., et al. (2006). Down-regulation of RUNX1, RUNX3 and CBFbeta in hepatocellular carcinomas in an early stage of hepatocarcinogenesis. Anticancer Res. 26, 3633-3643.
  87. Miyoshi, H., Ohira, M., Shimizu, K., Mitani, K., Hirai, H., Imai, T., Yokoyama, K., Soeda, E., and Ohki, M. (1995). Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res. 23, 2762-2769. https://doi.org/10.1093/nar/23.14.2762
  88. Miyoshi, H., Shimizu, K., Kozu, T., Maseki, N., Kaneko, Y., and Ohki, M. (1991). t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc. Natl. Acad. Sci. U. S. A. 88, 10431-10434. https://doi.org/10.1073/pnas.88.23.10431
  89. Monteiro, R., Pinheiro, P., Joseph, N., Peterkin, T., Koth, J., Repapi, E., Bonkhofer, F., Kirmizitas, A., and Patient, R. (2016). Transforming growth factor beta drives hemogenic endothelium programming and the transition to hematopoietic stem cells. Dev. Cell 38, 358-370. https://doi.org/10.1016/j.devcel.2016.06.024
  90. Morita, K., Maeda, S., Suzuki, K., Kiyose, H., Taniguchi, J., Liu, P.P., Sugiyama, H., Adachi, S., and Kamikubo, Y. (2017a). Paradoxical enhancement of leukemogenesis in acute myeloid leukemia with moderately attenuated RUNX1 expressions. Blood Adv. 1, 1440-1451. https://doi.org/10.1182/bloodadvances.2017007591
  91. Morita, K., Suzuki, K., Maeda, S., Matsuo, A., Mitsuda, Y., Tokushige, C., Kashiwazaki, G., Taniguchi, J., Maeda, R., Noura, M., et al. (2017b). Genetic regulation of the RUNX transcription factor family has antitumor effects. J. Clin. Invest. 127, 2815-2828. https://doi.org/10.1172/JCI91788
  92. Mukouyama, Y., Chiba, N., Hara, T., Okada, H., Ito, Y., Kanamaru, R., Miyajima, A., Satake, M., and Watanabe, T. (2000). The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region. Dev. Biol. 220, 27-36. https://doi.org/10.1006/dbio.2000.9617
  93. Nagata, T., Gupta, V., Sorce, D., Kim, W.Y., Sali, A., Chait, B.T., Shigesada, K., Ito, Y., and Werner, M.H. (1999). Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain. Nat. Struct. Biol. 6, 615-619. https://doi.org/10.1038/10658
  94. Navarro-Montero, O., Ayllon, V., Lamolda, M., Lopez-Onieva, L., Montes, R., Bueno, C., Ng, E., Guerrero-Carreno, X., Romero, T., Romero-Moya, D., et al. (2017). RUNX1c regulates hematopoietic differentiation of human pluripotent stem cells possibly in cooperation with proinflammatory signaling. Stem Cells 35, 2253-2266. https://doi.org/10.1002/stem.2700
  95. Neil, J.C., Gilroy, K., Borland, G., Hay, J., Terry, A., and Kilbey, A. (2017). The RUNX genes as conditional oncogenes: insights from retroviral targeting and mouse models. Adv. Exp. Med. Biol. 962, 247-264. https://doi.org/10.1007/978-981-10-3233-2_16
  96. Ng, E.S., Azzola, L., Bruveris, F.F., Calvanese, V., Phipson, B., Vlahos, K., Hirst, C., Jokubaitis, V.J., Yu, Q.C., Maksimovic, J., et al. (2016). Differentiation of human embryonic stem cells to HOXA(+) hemogenic vasculature that resembles the aorta-gonad-mesonephros. Nat. Biotechnol. 34, 1168-1179. https://doi.org/10.1038/nbt.3702
  97. Nieke, S., Yasmin, N., Kakugawa, K., Yokomizo, T., Muroi, S., and Taniuchi, I. (2017). Unique N-terminal sequences in two Runx1 isoforms are dispensable for Runx1 function. BMC Dev. Biol. 17, 14. https://doi.org/10.1186/s12861-017-0156-y
  98. Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L.B., Martin, S., Wedge, D.C., et al. (2016). Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534, 47-54. https://doi.org/10.1038/nature17676
  99. Niki, M., Okada, H., Takano, H., Kuno, J., Tani, K., Hibino, H., Asano, S., Ito, Y., Satake, M., and Noda, T. (1997). Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor. Proc. Natl. Acad. Sci. U. S. A. 94, 5697-5702. https://doi.org/10.1073/pnas.94.11.5697
  100. North, T., Gu, T.L., Stacy, T., Wang, Q., Howard, L., Binder, M., Marin-Padilla, M., and Speck, N.A. (1999). Cbfa2 is required for the formation of intraaortic hematopoietic clusters. Development 126, 2563-2575. https://doi.org/10.1242/dev.126.11.2563
  101. Ogawa, E., Inuzuka, M., Maruyama, M., Satake, M., Naito-Fujimoto, M., Ito, Y., and Shigesada, K. (1993a). Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha. Virology 194, 314-331. https://doi.org/10.1006/viro.1993.1262
  102. Ogawa, E., Maruyama, M., Kagoshima, H., Inuzuka, M., Lu, J., Satake, M., Shigesada, K., and Ito, Y. (1993b). PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc. Natl. Acad. Sci. U. S. A. 90, 6859-6863. https://doi.org/10.1073/pnas.90.14.6859
  103. Okuda, T., van Deursen, J., Hiebert, S.W., Grosveld, G., and Downing, J.R. (1996). AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321-330. https://doi.org/10.1016/S0092-8674(00)80986-1
  104. Ottersbach, K. (2019). Endothelial-to-haematopoietic transition: an update on the process of making blood. Biochem. Soc. Trans. 47, 591-601. https://doi.org/10.1042/BST20180320
  105. Patel, J.P., Gonen, M., Figueroa, M.E., Fernandez, H., Sun, Z., Racevskis, J., Van Vlierberghe, P., Dolgalev, I., Thomas, S., Aminova, O., et al. (2012). Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079-1089. https://doi.org/10.1056/NEJMoa1112304
  106. Pegg, H.J., Harrison, H., Rogerson, C., and Shore, P. (2019). The RUNX transcriptional coregulator, CBFbeta, suppresses migration of ER(+) breast cancer cells by repressing ERalpha-mediated expression of the migratory factor TFF1. Mol. Cancer Res. 17, 1015-1023. https://doi.org/10.1158/1541-7786.MCR-18-1039
  107. Pereira, B., Chin, S.F., Rueda, O.M., Vollan, H.K., Provenzano, E., Bardwell, H.A., Pugh, M., Jones, L., Russell, R., Sammut, S.J., et al. (2016). The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes. Nat. Commun. 7, 11479. https://doi.org/10.1038/ncomms11479
  108. Planaguma, J., Diaz-Fuertes, M., Gil-Moreno, A., Abal, M., Monge, M., Garcia, A., Baro, T., Thomson, T.M., Xercavins, J., Alameda, F., et al. (2004). A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res. 64, 8846-8853. https://doi.org/10.1158/0008-5472.CAN-04-2066
  109. Planaguma, J., Gonzalez, M., Doll, A., Monge, M., Gil-Moreno, A., Baro, T., Garcia, A., Xercavins, J., Alameda, F., Abal, M., et al. (2006). The upregulation profiles of p21WAF1/CIP1 and RUNX1/AML1 correlate with myometrial infiltration in endometrioid endometrial carcinoma. Hum. Pathol. 37, 1050-1057. https://doi.org/10.1016/j.humpath.2006.03.007
  110. Pozner, A., Goldenberg, D., Negreanu, V., Le, S.Y., Elroy-Stein, O., Levanon, D., and Groner, Y. (2000). Transcription-coupled translation control of AML1/RUNX1 is mediated by cap- and internal ribosome entry sitedependent mechanisms. Mol. Cell. Biol. 20, 2297-2307. https://doi.org/10.1128/MCB.20.7.2297-2307.2000
  111. Pozner, A., Lotem, J., Xiao, C., Goldenberg, D., Brenner, O., Negreanu, V., Levanon, D., and Groner, Y. (2007). Developmentally regulated promoterswitch transcriptionally controls Runx1 function during embryonic hematopoiesis. BMC Dev. Biol. 7, 84. https://doi.org/10.1186/1471-213X-7-84
  112. Ptasinska, A., Assi, S.A., Martinez-Soria, N., Imperato, M.R., Piper, J., Cauchy, P., Pickin, A., James, S.R., Hoogenkamp, M., Williamson, D., et al. (2014). Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Rep. 8, 1974-1988. https://doi.org/10.1016/j.celrep.2014.08.024
  113. Ramaswamy, S., Ross, K.N., Lander, E.S., and Golub, T.R. (2003). A molecular signature of metastasis in primary solid tumors. Nat. Genet. 33, 49-54. https://doi.org/10.1038/ng1060
  114. Rennert, J., Coffman, J.A., Mushegian, A.R., and Robertson, A.J. (2003). The evolution of Runx genes I. A comparative study of sequences from phylogenetically diverse model organisms. BMC Evol. Biol. 3, 4. https://doi.org/10.1186/1471-2148-3-4
  115. Riggio, A.I. and Blyth, K. (2017). The enigmatic role of RUNX1 in femalerelated cancers - current knowledge & future perspectives. FEBS J. 284, 2345-2362. https://doi.org/10.1111/febs.14059
  116. Robinson, H.M., Broadfield, Z.J., Cheung, K.L., Harewood, L., Harris, R.L., Jalali, G.R., Martineau, M., Moorman, A.V., Taylor, K.E., Richards, S., et al. (2003). Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 17, 2249-2250. https://doi.org/10.1038/sj.leu.2403140
  117. Rody, A., Karn, T., Liedtke, C., Pusztai, L., Ruckhaeberle, E., Hanker, L., Gaetje, R., Solbach, C., Ahr, A., Metzler, D., et al. (2011). A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res. 13, R97. https://doi.org/10.1186/bcr3035
  118. Sakakura, C., Hagiwara, A., Miyagawa, K., Nakashima, S., Yoshikawa, T., Kin, S., Nakase, Y., Ito, K., Yamagishi, H., Yazumi, S., et al. (2005). Frequent downregulation of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Int. J. Cancer 113, 221-228. https://doi.org/10.1002/ijc.20551
  119. Salarpour, F., Goudarzipour, K., Mohammadi, M.H., Ahmadzadeh, A., Faraahi, S., and Farsani, M.A. (2017). Evaluation of CCAAT/enhancer binding protein (C/EBP) alpha (CEBPA) and runt-related transcription factor 1 (RUNX1) expression in patients with de novo acute myeloid leukemia. Ann. Hum. Genet. 81, 276-283. https://doi.org/10.1111/ahg.12210
  120. Sasaki, K., Yagi, H., Bronson, R.T., Tominaga, K., Matsunashi, T., Deguchi, K., Tani, Y., Kishimoto, T., and Komori, T. (1996). Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proc. Natl. Acad. Sci. U. S. A. 93, 12359-12363. https://doi.org/10.1073/pnas.93.22.12359
  121. Scheitz, C.J., Lee, T.S., McDermitt, D.J., and Tumbar, T. (2012). Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 31, 4124-4139. https://doi.org/10.1038/emboj.2012.270
  122. Schnittger, S., Dicker, F., Kern, W., Wendland, N., Sundermann, J., Alpermann, T., Haferlach, C., and Haferlach, T. (2011). RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood 117, 2348-2357. https://doi.org/10.1182/blood-2009-11-255976
  123. Shang, Y., Zhao, X., Xu, X., Xin, H., Li, X., Zhai, Y., He, D., Jia, B., Chen, W., and Chang, Z. (2009). CHIP functions an E3 ubiquitin ligase of Runx1. Biochem. Biophys. Res. Commun. 386, 242-246. https://doi.org/10.1016/j.bbrc.2009.06.043
  124. Sood, R., Kamikubo, Y., and Liu, P. (2017). Role of RUNX1 in hematological malignancies. Blood 129, 2070-2082. https://doi.org/10.1182/blood-2016-10-687830
  125. Soulier, J., Trakhtenbrot, L., Najfeld, V., Lipton, J.M., Mathew, S., Avet- Loiseau, H., De Braekeleer, M., Salem, S., Baruchel, A., Raimondi, S.C., et al. (2003). Amplification of band q22 of chromosome 21, including AML1, in older children with acute lymphoblastic leukemia: an emerging molecular cytogenetic subgroup. Leukemia 17, 1679-1682. https://doi.org/10.1038/sj.leu.2403000
  126. Sroczynska, P., Lancrin, C., Kouskoff, V., and Lacaud, G. (2009). The differential activities of Runx1 promoters define milestones during embryonic hematopoiesis. Blood 114, 5279-5289. https://doi.org/10.1182/blood-2009-05-222307
  127. Sun, C.C., Li, S.J., Chen, Z.L., Li, G., Zhang, Q., and Li, D.J. (2019). Expression and prognosis analyses of runt-related transcription factor family in human leukemia. Mol. Ther. Oncolytics 12, 103-111. https://doi.org/10.1016/j.omto.2018.12.008
  128. Swiers, G., Baumann, C., O'Rourke, J., Giannoulatou, E., Taylor, S., Joshi, A., Moignard, V., Pina, C., Bee, T., Kokkaliaris, K.D., et al. (2013). Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. Nat. Commun. 4, 2924. https://doi.org/10.1038/ncomms3924
  129. Tachibana, M., Tezuka, C., Muroi, S., Nishimoto, S., Katsumoto, T., Nakajima, A., Kitabayashi, I., and Taniuchi, I. (2008). Phosphorylation of Runx1 at Ser249, Ser266, and Ser276 is dispensable for bone marrow hematopoiesis and thymocyte differentiation. Biochem. Biophys. Res. Commun. 368, 536-542. https://doi.org/10.1016/j.bbrc.2008.01.124
  130. Tahirov, T.H., Inoue-Bungo, T., Morii, H., Fujikawa, A., Sasaki, M., Kimura, K., Shiina, M., Sato, K., Kumasaka, T., Yamamoto, M., et al. (2001). Structural analyses of DNA recognition by the AML1/Runx-1 runt domain and its allosteric control by CBFbeta. Cell 104, 755-767. https://doi.org/10.1016/S0092-8674(01)00271-9
  131. Takayama, K., Suzuki, T., Tsutsumi, S., Fujimura, T., Urano, T., Takahashi, S., Homma, Y., Aburatani, H., and Inoue, S. (2015). RUNX1, an androgenand EZH2-regulated gene, has differential roles in AR-dependent and -independent prostate cancer. Oncotarget 6, 2263-2276. https://doi.org/10.18632/oncotarget.2949
  132. Tanaka, T., Kurokawa, M., Ueki, K., Tanaka, K., Imai, Y., Mitani, K., Okazaki, K., Sagata, N., Yazaki, Y., Shibata, Y., et al. (1996). The extracellular signalregulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability. Mol. Cell. Biol. 16, 3967-3979. https://doi.org/10.1128/MCB.16.7.3967
  133. Tang, J.L., Hou, H.A., Chen, C.Y., Liu, C.Y., Chou, W.C., Tseng, M.H., Huang, C.F., Lee, F.Y., Liu, M.C., Yao, M., et al. (2009). AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 114, 5352-5361. https://doi.org/10.1182/blood-2009-05-223784
  134. Taniuchi, I., Osato, M., and Ito, Y. (2012). Runx1: no longer just for leukemia. EMBO J. 31, 4098-4099. https://doi.org/10.1038/emboj.2012.282
  135. Tay, L.S., Krishnan, V., Sankar, H., Chong, Y.L., Chuang, L.S.H., Tan, T.Z., Kolinjivadi, A.M., Kappei, D., and Ito, Y. (2018). RUNX poly(ADP-Ribosyl) ation and BLM interaction facilitate the fanconi anemia pathway of DNA repair. Cell Rep. 24, 1747-1755. https://doi.org/10.1016/j.celrep.2018.07.038
  136. Telfer, J.C. and Rothenberg, E.V. (2001). Expression and function of a stem cell promoter for the murine CBFalpha2 gene: distinct roles and regulation in natural killer and T cell development. Dev. Biol. 229, 363-382. https://doi.org/10.1006/dbio.2000.9991
  137. van Bragt, M.P., Hu, X., Xie, Y., and Li, Z. (2014). RUNX1, a transcription factor mutated in breast cancer, controls the fate of ER-positive mammary luminal cells. Elife 3, e03881. https://doi.org/10.7554/eLife.03881
  138. Vu, L.P., Perna, F., Wang, L., Voza, F., Figueroa, M.E., Tempst, P., Erdjument- Bromage, H., Gao, R., Chen, S., Paietta, E., et al. (2013). PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep. 5, 1625-1638. https://doi.org/10.1016/j.celrep.2013.11.025
  139. Wang, L., Brugge, J.S., and Janes, K.A. (2011). Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc. Natl. Acad. Sci. U. S. A. 108, E803-E812. https://doi.org/10.1073/pnas.1103423108
  140. Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A.H., and Speck, N.A. (1996a). 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. 93, 3444-3449. https://doi.org/10.1073/pnas.93.8.3444
  141. 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. (1996b). The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell 87, 697-708. https://doi.org/10.1016/S0092-8674(00)81389-6
  142. Wang, S., Wang, Q., Crute, B.E., Melnikova, I.N., Keller, S.R., and Speck, N.A. (1993). Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol. Cell. Biol. 13, 3324-3339. https://doi.org/10.1128/MCB.13.6.3324
  143. Wee, H.J., Voon, D.C., Bae, S.C., and Ito, Y. (2008). PEBP2-beta/CBF-betadependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood 112, 3777-3787. https://doi.org/10.1182/blood.v112.11.3777.3777
  144. Yamaguchi, Y., Kurokawa, M., Imai, Y., Izutsu, K., Asai, T., Ichikawa, M., Yamamoto, G., Nitta, E., Yamagata, T., Sasaki, K., et al. (2004). AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J. Biol. Chem. 279, 15630-15638. https://doi.org/10.1074/jbc.M400355200
  145. Yan, J., Liu, Y., Lukasik, S.M., Speck, N.A., and Bushweller, J.H. (2004). CBFbeta allosterically regulates the Runx1 Runt domain via a dynamic conformational equilibrium. Nat. Struct. Mol. Biol. 11, 901-906. https://doi.org/10.1038/nsmb819
  146. Yeh, H.Y., Cheng, S.W., Lin, Y.C., Yeh, C.Y., Lin, S.F. and Soo, V.W. (2009). Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency. BMC Med. Genomics 2, 70. https://doi.org/10.1186/1755-8794-2-70
  147. Yokomizo, T., Hasegawa, K., Ishitobi, H., Osato, M., Ema, M., Ito, Y., Yamamoto, M., and Takahashi, S. (2008). Runx1 is involved in primitive erythropoiesis in the mouse. Blood 111, 4075-4080. https://doi.org/10.1182/blood-2007-05-091637
  148. Yonezawa, T., Takahashi, H., Shikata, S., Liu, X., Tamura, M., Asada, S., Fukushima, T., Fukuyama, T., Tanaka, Y., Sawasaki, T., et al. (2017). The ubiquitin ligase STUB1 regulates stability and activity of RUNX1 and RUNX1-RUNX1T1. J. Biol. Chem. 292, 12528-12541. https://doi.org/10.1074/jbc.M117.785675
  149. Yoshimi, M., Goyama, S., Kawazu, M., Nakagawa, M., Ichikawa, M., Imai, Y., Kumano, K., Asai, T., Mulloy, J.C., Kraft, A.S., et al. (2012). Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation. Eur. J. Immunol. 42, 1044-1050. https://doi.org/10.1002/eji.201040746
  150. Zeng, Y., He, J., Bai, Z., Li, Z., Gong, Y., Liu, C., Ni, Y., Du, J., Ma, C., Bian, L., et al. (2019). Tracing the first hematopoietic stem cell generation in human embryo by single-cell RNA sequencing. Cell Res. 29, 881-894. https://doi.org/10.1038/s41422-019-0228-6
  151. Zhang, Y., Biggs, J.R., and Kraft, A.S. (2004). Phorbol ester treatment of K562 cells regulates the transcriptional activity of AML1c through phosphorylation. J. Biol. Chem. 279, 53116-53125. https://doi.org/10.1074/jbc.M405502200
  152. Zhao, X., Jankovic, V., Gural, A., Huang, G., Pardanani, A., Menendez, S., Zhang, J., Dunne, R., Xiao, A., Erdjument-Bromage, H., et al. (2008). Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. Genes Dev. 22, 640-653. https://doi.org/10.1101/gad.1632608
  153. Zhou, T., Luo, M., Cai, W., Zhou, S., Feng, D., Xu, C., and Wang, H. (2018). Runt-related transcription factor 1 (RUNX1) promotes TGF-beta-induced renal tubular epithelial-to-mesenchymal transition (EMT) and renal fibrosis through the PI3K subunit p110delta. EBioMedicine 31, 217-225. https://doi.org/10.1016/j.ebiom.2018.04.023
  154. Zovein, A.C., Hofmann, J.J., Lynch, M., French, W.J., Turlo, K.A., Yang, Y., Becker, M.S., Zanetta, L., Dejana, E., Gasson, J.C., et al. (2008). Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell 3, 625-636. https://doi.org/10.1016/j.stem.2008.09.018

Cited by

  1. RUNX1 marks a luminal castration-resistant lineage established at the onset of prostate development vol.9, 2020, https://doi.org/10.7554/elife.60225
  2. Targeting RUNX1 in acute myeloid leukemia: preclinical innovations and therapeutic implications vol.25, pp.4, 2021, https://doi.org/10.1080/14728222.2021.1915991
  3. ERK Phosphorylation Regulates the Aml1/Runx1 Splice Variants and the TRP Channels Expression during the Differentiation of Glioma Stem Cell Lines vol.10, pp.8, 2021, https://doi.org/10.3390/cells10082052
  4. Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia vol.14, pp.1, 2020, https://doi.org/10.1186/s13045-021-01051-z