Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells

Impact on response to chemotherapy

Isabella Spinello, Maria Teresa Quaranta, Rosa Paolillo, Elvira Pelosi, Anna Maria Cerio, Ernestina Saulle, Francesco Lo Coco, Ugo Testa, Catherine Labbaye

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1160-1171
Number of pages12
JournalHaematologica
Volume100
Issue number9
DOIs
Publication statusPublished - Sep 7 2015

Fingerprint

MicroRNAs
Drug Therapy
Leukemia, Monocytic, Acute
Hypoxia-Inducible Factor 1
Pharmaceutical Preparations
Hypoxia
Cell Hypoxia
Cell Line
Chemokine Receptors
Myeloid Cells
Acute Myeloid Leukemia
Monocytes
Cell Survival
Up-Regulation
Bone Marrow

ASJC Scopus subject areas

  • Hematology

Cite this

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells : Impact on response to chemotherapy. / Spinello, Isabella; Quaranta, Maria Teresa; Paolillo, Rosa; Pelosi, Elvira; Cerio, Anna Maria; Saulle, Ernestina; Coco, Francesco Lo; Testa, Ugo; Labbaye, Catherine.

In: Haematologica, Vol. 100, No. 9, 07.09.2015, p. 1160-1171.

Research output: Contribution to journalArticle

Spinello, I, Quaranta, MT, Paolillo, R, Pelosi, E, Cerio, AM, Saulle, E, Coco, FL, Testa, U & Labbaye, C 2015, 'Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: Impact on response to chemotherapy', Haematologica, vol. 100, no. 9, pp. 1160-1171. https://doi.org/10.3324/haematol.2014.120295
Spinello, Isabella ; Quaranta, Maria Teresa ; Paolillo, Rosa ; Pelosi, Elvira ; Cerio, Anna Maria ; Saulle, Ernestina ; Coco, Francesco Lo ; Testa, Ugo ; Labbaye, Catherine. / Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells : Impact on response to chemotherapy. In: Haematologica. 2015 ; Vol. 100, No. 9. pp. 1160-1171.
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AU - Pelosi, Elvira

AU - Cerio, Anna Maria

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AU - Labbaye, Catherine

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