The enzymatic activities of CD38 enhance CLL growth and trafficking: implications for therapeutic targeting

The ecto-enzyme CD38 is a marker of unfavorable prognosis for chronic lymphocytic leukemia (CLL) patients and an indicator of activation and proliferation of leukemic cells. Here we show that CD38 is enzymatically active in primary CLL cells and that its forced expression increases disease aggressiveness in a xenograft model. The effect is completely lost when using an enzyme deficient version of CD38 with a single amino-acid mutation. Through the enzymatic conversion of NAD, CD38 increases cytoplasmic Ca2+ concentrations, positively influencing proliferation, chemotaxis, adhesion and matrix digestion. Inhibition of the enzymatic activities of CD38 using the flavonoid kuromanin blocks CLL homing. In a short-term xenograft model using primary cells, kuromanin treatment traps CLL cells in the blood, increasing responses to chemotherapy. Microarrays were performed comparing genetic signature derived from Mec-1 cell line variants, generated infecting cells by lentiviruses carrying the genetic material for a wild-type (CD38WT ) or an enzymatically-inactive form of CD38 (CD38M), grown in vitro and in vivo in NSG mice. GFP+ Mec-1 clones (Mec-1/GFP) were generated with the same protocol and used as control.