Epigenetic mechanisms in leukemia

Sayyed K. Zaidi, Daniel J. Trombly, Christopher R. Dowdy, Jane B. Lian, Janet L. Stein, Andre J van Wijnen, Gary S. Stein

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Focal organization of regulatory machinery within the interphase nucleus is linked to biological responsiveness and perturbed in cancer. Lineage determinant Runx proteins organize and assemble multi-protein complexes at sites of transcription within the nucleus and regulate both RNA polymerase II- and I-mediated gene expression. In addition, Runx proteins epigenetically control lineage determining transcriptional programs including: 1) architectural organization of macromolecular complexes in interphase, 2) regulation of gene expression through bookmarking during mitosis, and 3) microRNA-mediated translational control in the interphase nucleus. These mechanisms are compromised with the onset and progression of cancer. For example, the oncogenic AML1-ETO protein, which results from a chromosomal translocation between chromosomes 8 and 21, is expressed in nearly 25% of all acute myelogenous leukemias, disrupts Runx1 subnuclear localization during interphase and compromises transcriptional regulation. Epigenetically, the leukemic protein redirects the Runx1 DNA binding domain to leukemia-specific nuclear microenvironments, modifies regulatory protein accessibility to Runx1 target genes by imprinting repressive chromatin marks, and deregulates the microRNA (miR) profile of diseased myeloid cells. Consequently, the entire Runx1-dependent transcriptional program of myeloid cells is deregulated leading to onset and progression of acute myeloid leukemia and maintenance of leukemic phenotype. We discuss the potential of modified epigenetic landscape of leukemic cells as a viable therapeutic target.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalAdvances in Biological Regulation
Volume52
Issue number3
DOIs
StatePublished - Sep 2012
Externally publishedYes

Fingerprint

Interphase
Epigenomics
Core Binding Factor alpha Subunits
Leukemia
Myeloid Cells
MicroRNAs
Acute Myeloid Leukemia
Core Binding Factor Alpha 2 Subunit
RNA Polymerase I
Macromolecular Substances
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 8
Genetic Translocation
Proteins
RNA Polymerase II
Gene Expression Regulation
Mitosis
Chromatin
Neoplasms
Maintenance

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology
  • Molecular Medicine

Cite this

Zaidi, S. K., Trombly, D. J., Dowdy, C. R., Lian, J. B., Stein, J. L., van Wijnen, A. J., & Stein, G. S. (2012). Epigenetic mechanisms in leukemia. Advances in Biological Regulation, 52(3), 369-376. https://doi.org/10.1016/j.jbior.2012.05.001

Epigenetic mechanisms in leukemia. / Zaidi, Sayyed K.; Trombly, Daniel J.; Dowdy, Christopher R.; Lian, Jane B.; Stein, Janet L.; van Wijnen, Andre J; Stein, Gary S.

In: Advances in Biological Regulation, Vol. 52, No. 3, 09.2012, p. 369-376.

Research output: Contribution to journalArticle

Zaidi, SK, Trombly, DJ, Dowdy, CR, Lian, JB, Stein, JL, van Wijnen, AJ & Stein, GS 2012, 'Epigenetic mechanisms in leukemia', Advances in Biological Regulation, vol. 52, no. 3, pp. 369-376. https://doi.org/10.1016/j.jbior.2012.05.001
Zaidi SK, Trombly DJ, Dowdy CR, Lian JB, Stein JL, van Wijnen AJ et al. Epigenetic mechanisms in leukemia. Advances in Biological Regulation. 2012 Sep;52(3):369-376. https://doi.org/10.1016/j.jbior.2012.05.001
Zaidi, Sayyed K. ; Trombly, Daniel J. ; Dowdy, Christopher R. ; Lian, Jane B. ; Stein, Janet L. ; van Wijnen, Andre J ; Stein, Gary S. / Epigenetic mechanisms in leukemia. In: Advances in Biological Regulation. 2012 ; Vol. 52, No. 3. pp. 369-376.
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