Expansion of Primary Human AML by Aryl Hydrocarbon Receptor Antagonism Minimally Affects Leukemic Transcriptional Profiles but Alters Cellular Metabolism

Authors

  • Fanny L. Casado McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
  • Kyle R. Salci McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
  • Zoya Shapovalova McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
  • Borhane Guezguez McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
  • Tony J. Collins McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada
  • Mickie Bhatia McMaster Stem Cell and Cancer Research Institute, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada and Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

DOI:

https://doi.org/10.12974/2312-5411.2015.02.01.2

Keywords:

Acute myeloid leukemia, aryl hydrocarbon receptor antagonism, cellular metabolism, ex vivo expansion, gene expression, oxidative phosphorylation, StemRegenin1.

Abstract

Small molecule-based antagonism of the aryl hydrocarbon receptor (AHR) by StemRegenin1 (SR1) promotes ex vivo expansion and maintenance of primary human hematopoietic stem cells (HSCs) as well as acute myeloid leukemia (AML) cells. However, basis and nature of SR1 induced expansion of human AML remains unknown. Here, global expression profiling on 7 clinically diverse human AML patient samples treated ex vivo with a synthesized analog of SR1 (aSR1) uncovered that only as few as 750 genes were differentially regulated. Uniquely, aSR1 treatment did not modulate self-renewal associated pathways including Hedgehog, Notch or Wnt across patient samples, but instead resulted in overall upregulation of the oxidative phosphorylation metabolic pathway. Higher oxygen consumption rates, along with increased sensitivity to the chemotherapeutic agent cytarabine (AraC) validated that aSR1-induced transcriptional profiles lead to functional enhancement of oxidative phosphorylation. Our study reveals that aSR1 induces minor alterations to the leukemic transcriptional profile leading to a shift in cellular metabolism. This finding should further instruct use of SR1-mediated expansion for mechanistic studies of leukemic self-renewal and the development of drug screening platforms using patient specific AML samples. 

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Published

2015-03-24

How to Cite

Casado, F. L., Salci, K. R., Shapovalova, Z., Guezguez, B., Collins, T. J., & Bhatia, M. (2015). Expansion of Primary Human AML by Aryl Hydrocarbon Receptor Antagonism Minimally Affects Leukemic Transcriptional Profiles but Alters Cellular Metabolism. Journal of Hematology Research, 2(1), 9–16. https://doi.org/10.12974/2312-5411.2015.02.01.2

Issue

Vol. 2 No. 1 (2015)

Section

Articles