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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mulloy, J. C. Articles by Nimer, S. D. Search for Related Content PubMed PubMed Citation Articles by Mulloy, J. C. Articles by Nimer, S. D. Related Collections Hematopoiesis and Stem Cells Neoplasia Plenary Papers Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2002, Vol. 99, No. 1, pp. 15-23 PLENARY PAPER The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells James C. Mulloy, Jörg Cammenga, Karen L. MacKenzie, Francisco J. Berguido, Malcolm A. S. Moore, and Stephen D. Nimer From the Laboratory of Molecular Hematopoiesis, Sloan-Kettering Institute; the Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center; and the Laboratory of Developmental Hematopoiesis, Cell Biology Program, Sloan-Kettering Institute, New York, NY. The acute myelogenous leukemia-1 (AML1)-ETO fusion protein is generated by the t(8;21), which is found in 40% of AMLs of the French-American-British M2 subtype. AML1-ETO interferes with the function of the AML1 (RUNX1, CBFA2) transcription factor in a dominant-negative fashion and represses transcription by binding its consensus DNA-binding site and via protein-protein interactions with other transcription factors. AML1 activity is critical for the development of definitive hematopoiesis, and haploinsufficiency of AML1 has been linked to a propensity to develop AML. Murine experiments suggest that AML1-ETO expression may not be sufficient for leukemogenesis; however, like the BCR-ABL isoforms, the cellular background in which these fusion proteins are expressed may be critical to the phenotype observed. Retroviral gene transfer was used to examine the effect of AML1-ETO on the in vitro behavior of human hematopoietic stem and progenitor cells. Following transduction of CD34+ cells, stem and progenitor cells were quantified in clonogenic assays, cytokine-driven expansion cultures, and long-term stromal cocultures. Expression of AML1-ETO inhibited colony formation by committed progenitors, but enhanced the growth of stem cells (cobblestone area-forming cells), resulting in a profound survival advantage of transduced over nontransduced cells. AML1-ETO-expressing cells retained progenitor activity and continued to express CD34 throughout the 5-week long-term culture. Thus, AML1-ETO enhances the self-renewal of pluripotent stem cells, the physiological target of many acute myeloid leukemias. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. M. Corsello, G. Roti, K. N. Ross, K. T. Chow, I. Galinsky, D. J. DeAngelo, R. M. Stone, A. L. Kung, T. R. Golub, and K. Stegmaier Identification of AML1-ETO modulators by chemical genomics Blood, June 11, 2009; 113(24): 6193 - 6205. [Abstract] [Full Text] [PDF] S. Park, W. Chen, T. Cierpicki, M. Tonelli, X. Cai, N. A. Speck, and J. H. Bushweller Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity Blood, April 9, 2009; 113(15): 3558 - 3567. [Abstract] [Full Text] [PDF] L. Roudaia, M. D. Cheney, E. Manuylova, W. Chen, M. Morrow, S. Park, C.-T. Lee, P. Kaur, O. Williams, J. H. Bushweller, et al. 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Mulloy p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death Blood, February 15, 2008; 111(4): 2190 - 2199. [Abstract] [Full Text] [PDF] Y.-Y. Kuo and Z.-F. Chang GATA-1 and Gfi-1B Interplay To Regulate Bcl-xL Transcription Mol. Cell. Biol., June 15, 2007; 27(12): 4261 - 4272. [Abstract] [Full Text] [PDF] C. Wichmann, L. Chen, M. Heinrich, D. Baus, E. Pfitzner, M. Zornig, O. G. Ottmann, and M. Grez Targeting the Oligomerization Domain of ETO Interferes with RUNX1/ETO Oncogenic Activity in t(8;21)-Positive Leukemic Cells Cancer Res., March 1, 2007; 67(5): 2280 - 2289. [Abstract] [Full Text] [PDF] R. Claus, M. Fliegauf, M. Stock, J. A. Duque, M. Kolanczyk, and M. Lubbert Inhibitors of DNA methylation and histone deacetylation independently relieve AML1/ETO-mediated lysozyme repression J. Leukoc. Biol., December 1, 2006; 80(6): 1462 - 1472. [Abstract] [Full Text] [PDF] J. R. Biggs, L. F. Peterson, Y. Zhang, A. S. Kraft, and D.-E. Zhang AML1/RUNX1 Phosphorylation by Cyclin-Dependent Kinases Regulates the Degradation of AML1/RUNX1 by the Anaphase-Promoting Complex Mol. Cell. Biol., October 15, 2006; 26(20): 7420 - 7429. [Abstract] [Full Text] [PDF] M. Wunderlich, O. Krejci, J. Wei, and J. C. Mulloy Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability Blood, September 1, 2006; 108(5): 1690 - 1697. [Abstract] [Full Text] [PDF] A. Takeda, C. Goolsby, and N. R. Yaseen NUP98-HOXA9 Induces Long-term Proliferation and Blocks Differentiation of Primary Human CD34+ Hematopoietic Cells. Cancer Res., July 1, 2006; 66(13): 6628 - 6637. [Abstract] [Full Text] [PDF] Y. Choi, K. E. Elagib, L. L. Delehanty, and A. N. Goldfarb Erythroid Inhibition by the Leukemic Fusion AML1-ETO Is Associated with Impaired Acetylation of the Major Erythroid Transcription Factor GATA-1. Cancer Res., March 15, 2006; 66(6): 2990 - 2996. [Abstract] [Full Text] [PDF] S. Schnittger, T. M. Kohl, T. Haferlach, W. Kern, W. Hiddemann, K. Spiekermann, and C. Schoch KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival Blood, March 1, 2006; 107(5): 1791 - 1799. [Abstract] [Full Text] [PDF] F. Ravandi and Z. Estrov Eradication of Leukemia Stem Cells as a New Goal of Therapy in Leukemia Clin. Cancer Res., January 15, 2006; 12(2): 340 - 344. [Abstract] [Full Text] [PDF] J. Cammenga, S. Horn, U. Bergholz, G. Sommer, P. Besmer, W. Fiedler, and C. Stocking Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate Blood, December 1, 2005; 106(12): 3958 - 3961. [Abstract] [Full Text] [PDF] J. R. Biggs, Y. Zhang, L. F. Peterson, M. Garcia, D.-E. Zhang, and A. S. Kraft Phosphorylation of AML1/RUNX1 Regulates Its Degradation and Nuclear Matrix Association Mol. Cancer Res., July 1, 2005; 3(7): 391 - 401. [Abstract] [Full Text] [PDF] J. C. Mulloy, V. Jankovic, M. Wunderlich, R. Delwel, J. Cammenga, O. Krejci, H. Zhao, P. J. M. Valk, B. Lowenberg, and S. D. Nimer AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion PNAS, March 15, 2005; 102(11): 4016 - 4021. [Abstract] [Full Text] [PDF] Y.-Y. Wang, G.-B. Zhou, T. Yin, B. Chen, J.-Y. Shi, W.-X. Liang, X.-L. Jin, J.-H. You, G. Yang, Z.-X. Shen, et al. AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec PNAS, January 25, 2005; 102(4): 1104 - 1109. [Abstract] [Full Text] [PDF] W. Sun and J. R. Downing Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors Blood, December 1, 2004; 104(12): 3565 - 3572. [Abstract] [Full Text] [PDF] T. S. Fenske, G. Pengue, V. Mathews, P. T. Hanson, S. E. Hamm, N. Riaz, and T. A. Graubert Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice PNAS, October 19, 2004; 101(42): 15184 - 15189. [Abstract] [Full Text] [PDF] A. Moldenhauer, R. C. Frank, J. Pinilla-Ibarz, G. Holland, P. Boccuni, D. A. Scheinberg, A. Salama, K. Seeger, M. A. S. Moore, and S. D. Nimer Histone deacetylase inhibition improves dendritic cell differentiation of leukemic blasts with AML1-containing fusion proteins J. Leukoc. Biol., September 1, 2004; 76(3): 623 - 633. [Abstract] [Full Text] [PDF] J. Zhang, M. Kalkum, S. Yamamura, B. T. Chait, and R. G. Roeder E Protein Silencing by the Leukemogenic AML1-ETO Fusion Protein Science, August 27, 2004; 305(5688): 1286 - 1289. [Abstract] [Full Text] [PDF] V. Ibanez, A. Sharma, S. Buonamici, A. Verma, S. Kalakonda, J. Wang, S. Kadkol, and Y. Saunthararajah AML1-ETO Decreases ETO-2 (MTG16) Interactions with Nuclear Receptor Corepressor, an Effect That Impairs Granulocyte Differentiation Cancer Res., July 1, 2004; 64(13): 4547 - 4554. [Abstract] [Full Text] [PDF] S. Tsuzuki, M. Seto, M. Greaves, and T. Enver Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice PNAS, June 1, 2004; 101(22): 8443 - 8448. [Abstract] [Full Text] [PDF] A. Moldenhauer, J-H Shieh, A. Pruss, A. Salama, and M.A.S. Moore Tumor Necrosis Factor Alpha Enhances the Adenoviral Transduction of CD34+ Hematopoietic Progenitor Cells Stem Cells, May 1, 2004; 22(3): 283 - 291. [Abstract] [Full Text] [PDF] F. Bernardin-Fried, T. Kummalue, S. Leijen, M. I. Collector, K. Ravid, and A. D. Friedman AML1/RUNX1 Increases During G1 to S Cell Cycle Progression Independent of Cytokine-dependent Phosphorylation and Induces Cyclin D3 Gene Expression J. Biol. Chem., April 9, 2004; 279(15): 15678 - 15687. [Abstract] [Full Text] [PDF] C. Muller-Tidow, B. Steffen, T. Cauvet, L. Tickenbrock, P. Ji, S. Diederichs, B. Sargin, G. Kohler, M. Stelljes, E. Puccetti, et al. Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells Mol. Cell. Biol., April 1, 2004; 24(7): 2890 - 2904. [Abstract] [Full Text] [PDF] M. Schwieger, J. Lohler, M. Fischer, U. Herwig, D. G. Tenen, and C. Stocking A dominant-negative mutant of C/EBP{alpha}, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse Blood, April 1, 2004; 103(7): 2744 - 2752. [Abstract] [Full Text] [PDF] J. C. Mulloy, J. Cammenga, F. J. Berguido, K. Wu, P. Zhou, R. L. Comenzo, S. Jhanwar, M. A. S. Moore, and S. D. Nimer Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element Blood, December 15, 2003; 102(13): 4369 - 4376. [Abstract] [Full Text] [PDF] O. Heidenreich, J. Krauter, H. Riehle, P. Hadwiger, M. John, G. Heil, H.-P. Vornlocher, and A. Nordheim AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells Blood, April 15, 2003; 101(8): 3157 - 3163. [Abstract] [Full Text] [PDF] M. Mizuki, J. Schwable, C. Steur, C. Choudhary, S. Agrawal, B. Sargin, B. Steffen, I. Matsumura, Y. Kanakura, F. D. Bohmer, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations Blood, April 15, 2003; 101(8): 3164 - 3173. [Abstract] [Full Text] [PDF] A. Tonks, L. Pearn, A. J. Tonks, L. Pearce, T. Hoy, S. Phillips, J. Fisher, J. R. Downing, A. K. Burnett, and R. L. Darley The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells Blood, January 15, 2003; 101(2): 624 - 632. [Abstract] [Full Text] [PDF] R. K. Vangala, M. S. Heiss-Neumann, J. S. Rangatia, S. M. Singh, C. Schoch, D. G. Tenen, W. Hiddemann, and G. Behre The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia Blood, January 1, 2003; 101(1): 270 - 277. [Abstract] [Full Text] [PDF] M. Schwieger, J. Lohler, J. Friel, M. Scheller, I. Horak, and C. Stocking AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency J. Exp. Med., November 4, 2002; 196(9): 1227 - 1240. [Abstract] [Full Text] [PDF] B. A. Hug, S. Y. D. Lee, E. L. Kinsler, J. Zhang, and M. A. Lazar Cooperative Function of Aml1-ETO Corepressor Recruitment Domains in the Expansion of Primary Bone Marrow Cells Cancer Res., May 1, 2002; 62(10): 2906 - 2912. [Abstract] [Full Text] [PDF]

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