This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ibañez, V. Articles by Saunthararajah, Y. Search for Related Content PubMed PubMed Citation Articles by Ibañez, V. Articles by Saunthararajah, Y.

AML1-ETO Decreases ETO-2 (MTG16) Interactions with Nuclear Receptor Corepressor, an Effect That Impairs Granulocyte Differentiation

¹ Section of Hematology/Oncology, Department of Medicine, and ² Department of Pathology, University of Illinois, Chicago, Illinois; ³ Department of Ophthalmology, University of Maryland, Baltimore, Maryland; and ⁴ Laboratory of Hematological Malignancy, State Key Laboratory of Experimental Hematology, Institute of Hematology, Chinese Academy of Medical Sciences

The t(8;21) chromosome abnormality in acute myeloid leukemia targets the AML1 and ETO genes to produce the leukemia fusion protein AML1-ETO. Another member of the ETO family, ETO-2/MTG16, is highly expressed in murine and human hematopoietic cells, bears >75% homology to ETO, and like ETO, contains a conserved MYND domain that interacts with the nuclear receptor corepressor (N-CoR). AML1-ETO prevents granulocyte but not macrophage differentiation of murine 32Dcl3 granulocyte/macrophage progenitors. One possible mechanism is recruitment of N-CoR to aberrantly repress AML1 target genes. We wished to examine another mechanism by which AML1-ETO might impair granulocyte differentiation. We demonstrate that AML1-ETO decreases interactions between ETO-2 and N-CoR. Furthermore, overexpression of ETO-2 relieves AML1-ETO-induced granulocyte differentiation arrest. This suggests that decreased interactions between ETO-2 and N-CoR may contribute to granulocyte differentiation impairment. The MYND domain coimmunoprecipitates with N-CoR and inhibits interactions between ETO-2 and N-CoR, presumably by occupying the ETO-2 binding site on N-CoR. This inhibition of ETO-2 interactions with N-CoR is specific because the MYND domain does not inhibit retinoic acid receptor interactions with N-CoR. To examine the effect of decreasing interactions between ETO-2 and N-CoR in hematopoietic cells, without effects of AML1-ETO such as direct repression of AML1 target genes, the MYND domain was expressed in 32Dcl3 and human CD34+ cells. The MYND domain prevented granulocyte but not macrophage differentiation of both 32Dcl3 and human CD34+ cells, recapitulating this effect of AML1-ETO. In conclusion, decreasing interactions between ETO-2 and N-CoR, an effect of AML1-ETO, inhibits granulocyte differentiation.

This article has been cited by other articles:

				B. J. Chyla, I. Moreno-Miralles, M. A. Steapleton, M. A. Thompson, S. Bhaskara, M. Engel, and S. W. Hiebert Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation Mol. Cell. Biol., October 15, 2008; 28(20): 6234 - 6247. [Abstract] [Full Text] [PDF]

				A. C. Moore, J. M. Amann, C. S. Williams, E. Tahinci, T. E. Farmer, J. A. Martinez, G. Yang, K. S. Luce, E. Lee, and S. W. Hiebert Myeloid Translocation Gene Family Members Associate with T-Cell Factors (TCFs) and Influence TCF-Dependent Transcription Mol. Cell. Biol., February 1, 2008; 28(3): 977 - 987. [Abstract] [Full Text] [PDF]

				L. F. Peterson, A. Boyapati, E.-Y. Ahn, J. R. Biggs, A. J. Okumura, M.-C. Lo, M. Yan, and D.-E. Zhang Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts Blood, August 1, 2007; 110(3): 799 - 805. [Abstract] [Full Text] [PDF]

				S. Minakhina, M. Druzhinina, and R. Steward Zfrp8, the Drosophila ortholog of PDCD2, functions in lymph gland development and controls cell proliferation Development, July 1, 2007; 134(13): 2387 - 2396. [Abstract] [Full Text] [PDF]

				L. F. Peterson, M. Yan, and D.-E. Zhang The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO Blood, May 15, 2007; 109(10): 4392 - 4398. [Abstract] [Full Text] [PDF]

				L. Vassen, T. Okayama, and T. Moroy Gfi1b:green fluorescent protein knock-in mice reveal a dynamic expression pattern of Gfi1b during hematopoiesis that is largely complementary to Gfi1 Blood, March 15, 2007; 109(6): 2356 - 2364. [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]