Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy.

Abstract

High expression of the chemokine receptor 4, CXCR4, associated with a negative prognosis in acute myeloid leukemia, is related to hypoxia. Because CXCR4 expression is under the post-transcriptional control of microRNA-146a in normal and leukemic monocytic cells, we first investigated the impact of hypoxia on microRNA-146a and CXCR4 expression during monocytopoiesis and in acute monocytic leukemia. We then analyzed the effects of hypoxia on drug sensitivity of CXCR4-expressing leukemic cells. We found that microRNA-146a is a target of hypoxia-inducible factor-1α or -2α in relation to the stage of monocytopoiesis and the level of hypoxia, and demonstrated the regulation of the microRNA-146a/CXCR4 pathway by hypoxia in monocytes derived from CD34(+) cells. Thus, in myeloid leukemic cell lines, hypoxia-mediated control of the microRNA-146a/CXCR4 pathway depends only on the capacity of hypoxia-inducible factor-1α to up-regulate microRNA-146a, which in turn decreases CXCR4 expression. However, at variance with normal monocytic cells and leukemic cell lines, in acute monocytic leukemia overexpressing CXCR4, hypoxia up-modulates microRNA-146a but fails to down-modulate CXCR4 expression. We then investigated the effect of hypoxia on the response of leukemic cells to chemotherapy alone or in combination with stromal-derived factor-1α. We found that hypoxia increases stromal-derived factor-1α-induced survival of leukemic cells by decreasing their sensitivity to anti-leukemic drugs. Altogether, our results demonstrate that hypoxia-mediated regulation of microRNA-146a, which controls CXCR4 expression in monocytic cells, is lost in acute monocytic leukemia, thus contributing to maintaining CXCR4 overexpression and protecting the cells from anti-leukemic drugs in the hypoxic bone marrow microenvironment.

• Authors: Isabella Spinello, Maria Teresa Quaranta, Rosa Paolillo, Elvira Pelosi, Anna Maria Cerio, Ernestina Saulle, Francesco Lo Coco, Ugo Testa, Catherine Labbaye
• Journal: Haematologica (Haematologica) Vol. 100 Issue 9 Pg. 1160-71 (Sep 2015) ISSN: 1592-8721 [Electronic] Italy
• PMID: 26045293 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Ferrata Storti Foundation.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• CXCR4 protein, human
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• MIRN146 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• RNA, Neoplasm
• Receptors, CXCR4
• endothelial PAS domain-containing protein 1

Topics

• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Hypoxia (drug effects)
• Female
• Gene Expression Regulation, Leukemic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Leukemia, Monocytic, Acute (drug therapy, metabolism, pathology)
• Male
• MicroRNAs (biosynthesis)
• Monocytes (metabolism, pathology)
• Neoplasm Proteins (biosynthesis)
• RNA, Neoplasm (biosynthesis)
• Receptors, CXCR4 (biosynthesis)
• U937 Cells