Genomic impact of transient low-dose decitabine treatment on primary AMLcells

Jeffery M. Klco, David H. Spencer, Tamara L. Lamprecht, Shawn M. Sarkaria, Todd Wylie, Vincent Magrini, Jasreet Hundal, Jason Walker, Nobish Varghese, Petra Erdmann-Gilmore, Cheryl F. Lichti, Matthew R. Meyer, R. Reid Townsend, Richard K. Wilson, Elaine R. Mardis, Timothy J. Ley

Research output: Contribution to journalArticle

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Abstract

Acute myeloid leukemia (AML) is characterized by dysregulated gene expression and abnormal patterns of DNAmethylation; the relationship between these events is unclear. Many AML patients are now being treated with hypomethylating agents, such as decitabine (DAC), although the mechanisms by which it induces remissions remain unknown. The goal of this study was to use a novel stromal coculture assay that can expand primary AML cells to identify the immediate changes induced by DAC with a dose (100nM) that decreases total 5-methylcytosine content and reactivates imprinted genes (without causing myeloid differentiation, which would confound downstream genomic analyses). Using array-based technologies, we found that DAC treatment caused global hypomethylation in all samples (with a preference for regions with higher levels of baseline methylation), yet there was limited correlation between changes in methylation and gene expression. Moreover, the patterns of methylation and gene expression across the samples were primarily determined by the intrinsic properties of the primary cells, rather than DAC treatment. Although DAC induces hypomethylation, we could not identify canonical target genes that are altered by DAC in primary AML cells, suggesting that the mechanism of action of DAC is more complex than previously recognized.

Original languageEnglish (US)
Pages (from-to)1633-1643
Number of pages11
JournalBlood
Volume121
Issue number9
DOIs
StatePublished - Feb 28 2013

Fingerprint

decitabine
Methylation
Acute Myeloid Leukemia
Gene expression
Myeloid Cells
Genes
Gene Expression
5-Methylcytosine
Assays
Therapeutics
Coculture Techniques
Technology

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Klco, J. M., Spencer, D. H., Lamprecht, T. L., Sarkaria, S. M., Wylie, T., Magrini, V., ... Ley, T. J. (2013). Genomic impact of transient low-dose decitabine treatment on primary AMLcells. Blood, 121(9), 1633-1643. https://doi.org/10.1182/blood-2012-09-459313

Genomic impact of transient low-dose decitabine treatment on primary AMLcells. / Klco, Jeffery M.; Spencer, David H.; Lamprecht, Tamara L.; Sarkaria, Shawn M.; Wylie, Todd; Magrini, Vincent; Hundal, Jasreet; Walker, Jason; Varghese, Nobish; Erdmann-Gilmore, Petra; Lichti, Cheryl F.; Meyer, Matthew R.; Townsend, R. Reid; Wilson, Richard K.; Mardis, Elaine R.; Ley, Timothy J.

In: Blood, Vol. 121, No. 9, 28.02.2013, p. 1633-1643.

Research output: Contribution to journalArticle

Klco, JM, Spencer, DH, Lamprecht, TL, Sarkaria, SM, Wylie, T, Magrini, V, Hundal, J, Walker, J, Varghese, N, Erdmann-Gilmore, P, Lichti, CF, Meyer, MR, Townsend, RR, Wilson, RK, Mardis, ER & Ley, TJ 2013, 'Genomic impact of transient low-dose decitabine treatment on primary AMLcells', Blood, vol. 121, no. 9, pp. 1633-1643. https://doi.org/10.1182/blood-2012-09-459313
Klco JM, Spencer DH, Lamprecht TL, Sarkaria SM, Wylie T, Magrini V et al. Genomic impact of transient low-dose decitabine treatment on primary AMLcells. Blood. 2013 Feb 28;121(9):1633-1643. https://doi.org/10.1182/blood-2012-09-459313
Klco, Jeffery M. ; Spencer, David H. ; Lamprecht, Tamara L. ; Sarkaria, Shawn M. ; Wylie, Todd ; Magrini, Vincent ; Hundal, Jasreet ; Walker, Jason ; Varghese, Nobish ; Erdmann-Gilmore, Petra ; Lichti, Cheryl F. ; Meyer, Matthew R. ; Townsend, R. Reid ; Wilson, Richard K. ; Mardis, Elaine R. ; Ley, Timothy J. / Genomic impact of transient low-dose decitabine treatment on primary AMLcells. In: Blood. 2013 ; Vol. 121, No. 9. pp. 1633-1643.
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