Abstract
Human myeloma cells express CD38 at high levels and grow in hypoxic niches inside the bone marrow. Myeloma cells respond to hypoxia with metabolic changes leading to aerobic glycolysis, thus reducing ATP and increasing NAD+. Our hypothesis is that these conditions favor the enzymatic pathways involved in the production of adenosine in the niche. Within the niche, NAD+ is able to activate a discontinuous adenosinergic pathway that relies upon CD38, CD203a, and CD73 or TRACP, according to the environmental pH. The observed variability in adenosine concentrations in bone marrow aspirates is a result of the interactions taking place among myeloma and other cells in the bone marrow niche. A pilot study showed that adenosine profiles differ during disease progression. Adenosine levels were significantly higher in the bone marrow plasma of patients with symptomatic myeloma and correlated with ISS staging, suggesting that adenosine is produced in the myeloma niche at micromolar levels by an ectoenzymatic network centered on CD38. Adenosine levels increase with disease aggressiveness, a finding that supports adenosine as a potential marker of myeloma progression.
Highlights
Multiple myeloma (MM) is characterized by accumulation of plasma cells (PC) in the bone marrow (BM) [1]
Adenosine in Aspirates from the BM Myeloma Niche Obtained from MM Patients
Plasma from BM biopsies was immediately pretreated for the High Pressure Liquid Chromatography (HPLC) assay, given the very short half-life of ADO and its rapid uptake by cells of the BM niche
Summary
Multiple myeloma (MM) is characterized by accumulation of plasma cells (PC) in the bone marrow (BM) [1] This proliferation of malignant PC is driven by an endless loop: myeloma-secreted products stimulate specialized cells in the BM myeloma cell niche, which in turn release soluble factors that modulate tumor cell proliferation and immune response [2]. The tumor environment contains high levels of extracellular nucleotides (ATP, NAD+), which serve intracellularly as building blocks for cell division and energy metabolism, but have been recognized as intercellular communicators and signal transducers [6] Nucleotides and their degradation products are believed to modulate communication between myeloma and normal cells, contributing to the immunocompromised state of MM patients [7]
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