Abstract 1348: CD38 regulates homing and engraftment in a mouse model of CLL

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is the result of a dynamic balance between proliferating cells in lymphoid organs and circulating cells resisting apoptosis. A critical step in the maintenance and progression of the disease is the re-circulation of leukemic cells from blood to growth-permissive niches. This process is controlled by a set of surface molecules expressed by CLL cells and modulated in response to environmental conditions. We previously showed that CD38, an enzyme and a receptor, functionally cooperates with the CXCL12/CXCR4 axis, increasing the ability of CLL cells to home to bone marrow and lymph nodes. Moreover, the use of anti-CD38 mAbs influences this cooperation, enhancing or impairing the chemotactic behavior of the neoplastic cells. New evidence also indicates that CD38 synergizes with the CD49d integrin, increasing adhesion of CLL cells to VCAM-1 or the CS-1 fibronectin fragment, two known ligands of CD49d. To complete the picture, CD38 expression marks a CLL subset with increased activity of MMP-9, the main matrix metalloproteinase expressed by CLL cells. Ligation of CD38 with specific antibodies increases MMP-9 secretion and hence the invasive properties of CLL cells. The effects on chemotaxis, adhesion and invasion are obtained through the modulation of a ERK1/2-dependent, PI-3K-independent pathway. The aim of this work is to confirm in an in vivo model the role played by CD38 in regulating CLL homing to specific niches and engraftment ability of leukemic cells. The CLL-like cell line Mec-1, constitutively CD38-/CD49d+, was compared to transfectants, generated both by lentiviral infections and by electroporation, stably expressing wild-type CD38, as well a mutant lacking enzyme activities. An in vivo model of immune-compromised mice was set-up, using the NOD/SCID/γ chain-/- (NSG) mice. Tumor cells were injected into the tail vein of 10-12 weeks old mice and left to engraft for 4 weeks. Results indicate that de novo expression of CD38 by Mec-1 cells increases growth kinetics in vivo with a higher proliferation rate and metastatic potential, as compared to the Mec-1 mock- cells. Mice injected with CD38+ Mec-1 cells show earlier signs of tumor burden and die sooner. Both these features are lost when the animals are injected with the enzyme-deficient variant of CD38, suggesting that the enzymatic activity is critical for in vivo growth and re-circulation of Mec-1 cells. Microarray data confirm that the genetic signature of the CD38-enzyme mutant overlaps with the wild-type cell line, clearly distinct from cells transfected with CD38. The latter cell line shows up-modulation of several genes involved in chemotaxis and adhesion. These results support the working hypothesis that CD38 is part of a complex network of molecules and signals, that regulate homing of leukemic cells to growth-permissive niches and represent the rationale for testing the in vivo impact of anti-CD38 mAbs or enzyme inhibitors as potential therapeutic tools. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1348. doi:1538-7445.AM2012-1348