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Blood Adv. 2016 Nov 22;1(1):47-61. doi: 10.1182/bloodadvances.2016000984. eCollection 2016 Nov 29.

Adenosine signaling mediates hypoxic responses in the chronic lymphocytic leukemia microenvironment.

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Department of Medical Sciences, University of Turin, Turin, Italy.
Human Genetics Foundation, Turin, Italy.
The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY.
Division of Hematology, Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.
Department of Hematology, Dubrava University Hospital, Zagreb, Croatia.
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy.
Department of Hematology, Weill Cornell Medicine, New York, NY; and.
Beth Israel Deaconess Medical Center, Harvard University, Boston, MA.


The chronic lymphocytic leukemia (CLL) niche is a closed environment where leukemic cells derive growth and survival signals through their interaction with macrophages and T lymphocytes. Here, we show that the CLL lymph node niche is characterized by overexpression and activation of HIF-1α, which increases adenosine generation and signaling, affecting tumor and host cellular responses. Hypoxia in CLL lymphocytes modifies central metabolic pathways, protects against drug-driven apoptosis, and induces interleukin 10 (IL-10) production. In myeloid cells, it forces monocyte differentiation to macrophages expressing IRF4, IDO, CD163, and CD206, hallmarks of the M2 phenotype, which promotes tumor progression. It also induces IL-6 production and enhances nurturing properties. Low oxygen levels decrease T-cell proliferation, promote glycolysis, and cause the appearance of a population of PD-1+ and IL-10-secreting T cells. Blockade of the A2A adenosine receptor counteracts these effects on all cell populations, making leukemic cells more susceptible to pharmacological agents while restoring immune competence and T-cell proliferation. Together, these results indicate that adenosine signaling through the A2A receptor mediates part of the effects of hypoxia. They also suggest that therapeutic strategies to inhibit the adenosinergic axis may be useful adjuncts to chemotherapy or tyrosine kinase inhibitors in the treatment of CLL patients.

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