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TLX1/HOX11-induced hematopoietic differentiation blockade

Oncogene volume 26, pages 4115–4123 (2007)Cite this article

Abstract

Aberrant expression of the human homeobox-containing proto-oncogene TLX1/HOX11 inhibits hematopoietic differentiation programs in a number of murine model systems. Here, we report the establishment of a murine erythroid progenitor cell line, iEBHX1S-4, developmentally arrested by regulatable TLX1 expression. Extinction of TLX1 expression released the iEBHX1S-4 differentiation block, allowing erythropoietin-dependent acquisition of erythroid markers and hemoglobin synthesis. Coordinated activation of erythroid transcriptional networks integrated by the acetyltransferase co-activator CREB-binding protein (CBP) was suggested by bioinformatic analysis of the upstream regulatory regions of several conditionally induced iEBHX1S-4 gene sets. In accord with this notion, CBP-associated acetylation of GATA-1, an essential regulator of erythroid differentiation, increased concomitantly with TLX1 downregulation. Coimmunoprecipitation experiments and glutathione-S-transferase pull-down assays revealed that TLX1 directly binds to CBP, and confocal laser microscopy demonstrated that the two proteins partially colocalize at intranuclear sites in iEBHX1S-4 cells. Notably, the distribution of CBP in conditionally blocked iEBHX1S-4 cells partially overlapped with chromatin marked by a repressive histone methylation pattern, and downregulation of TLX1 coincided with exit of CBP from these heterochromatic regions. Thus, we propose that TLX1-mediated differentiation arrest may be achieved in part through a mechanism that involves redirection of CBP and/or its sequestration in repressive chromatin domains.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, The George Washington University Medical Center, Washington, DC, USA

    I Riz, S S Akimov, K K Baxter, H J Lee & R G Hawley

  2. NanoDetection Technology, Knoxville, TN, USA

    S S Eaker

  3. Molecular Medicine Program, The George Washington University Medical Center, Washington, DC, USA

    K K Baxter & R G Hawley

  4. Genomics and Bioinformatics Program, The George Washington University Medical Center, Washington, DC, USA

    H J Lee

  5. Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, USA

    L Mariño-Ramírez & D Landsman

  6. Flow Cytometry Core Facility, The George Washington University Medical Center, Washington, DC, USA

    T S Hawley

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Correspondence to R G Hawley.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Riz, I., Akimov, S., Eaker, S. et al. TLX1/HOX11-induced hematopoietic differentiation blockade. Oncogene 26, 4115–4123 (2007). https://doi.org/10.1038/sj.onc.1210185

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