TLX1/HOX11-induced hematopoietic differentiation blockade

I. Riz, Sergey Akimov, S. S. Eaker, K. K. Baxter, H. J. Lee, L. Mariño-Ramírez, D. Landsman, T. S. Hawley, R. G. Hawley

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)4115-4123
Number of pages9
JournalOncogene
Volume26
Issue number28
DOIs
StatePublished - Jun 14 2007
Externally publishedYes

Fingerprint

CREB-Binding Protein
Confocal Microscopy
Chromatin
Down-Regulation
Erythroid Precursor Cells
Acetyltransferases
Proto-Oncogenes
Homeobox Genes
Gene Regulatory Networks
Nucleic Acid Regulatory Sequences
Acetylation
Erythropoietin
Glutathione Transferase
Computational Biology
Histones
Methylation
Hemoglobins
Cell Line
Genes

Keywords

  • CBP
  • Conditional differentiation block
  • Erythropoiesis
  • GATA-1
  • Repressive chromatin domains
  • TLX1/HOX11 oncogene

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Riz, I., Akimov, S., Eaker, S. S., Baxter, K. K., Lee, H. J., Mariño-Ramírez, L., ... Hawley, R. G. (2007). TLX1/HOX11-induced hematopoietic differentiation blockade. Oncogene, 26(28), 4115-4123. https://doi.org/10.1038/sj.onc.1210185

TLX1/HOX11-induced hematopoietic differentiation blockade. / Riz, I.; Akimov, Sergey; Eaker, S. S.; Baxter, K. K.; Lee, H. J.; Mariño-Ramírez, L.; Landsman, D.; Hawley, T. S.; Hawley, R. G.

In: Oncogene, Vol. 26, No. 28, 14.06.2007, p. 4115-4123.

Research output: Contribution to journalArticle

Riz, I, Akimov, S, Eaker, SS, Baxter, KK, Lee, HJ, Mariño-Ramírez, L, Landsman, D, Hawley, TS & Hawley, RG 2007, 'TLX1/HOX11-induced hematopoietic differentiation blockade', Oncogene, vol. 26, no. 28, pp. 4115-4123. https://doi.org/10.1038/sj.onc.1210185
Riz I, Akimov S, Eaker SS, Baxter KK, Lee HJ, Mariño-Ramírez L et al. TLX1/HOX11-induced hematopoietic differentiation blockade. Oncogene. 2007 Jun 14;26(28):4115-4123. https://doi.org/10.1038/sj.onc.1210185
Riz, I. ; Akimov, Sergey ; Eaker, S. S. ; Baxter, K. K. ; Lee, H. J. ; Mariño-Ramírez, L. ; Landsman, D. ; Hawley, T. S. ; Hawley, R. G. / TLX1/HOX11-induced hematopoietic differentiation blockade. In: Oncogene. 2007 ; Vol. 26, No. 28. pp. 4115-4123.
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