Publication Date:
2013-11-15
Description:
CD38 is a cell surface receptor and enzyme. As a receptor CD38 interacts with CD31 activating a well characterized signaling pathway. As an enzyme, it metabolizes NAD generating Ca2+ mobilizing messengers, including cADPR and ADPR. In CLL, CD38 acts as a negative prognostic marker: its expression by the leukemic component is associated with a more aggressive clinical course and a worse overall survival. We and others have shown that CD38 is also a critical element in the pathogenetic network underlying the disease by functioning as a compass which drives CLL cells to growth-favorable niches. This is accomplished through a physical and functional cooperation with chemokine receptors (e.g. CXCR4), integrins (e.g. CD49d) and matrix metalloproteases (MMP-9). Notwithstanding intense investigation in the field, the functional mechanisms through which CD38 regulates CLL homing remain unknown. To determine the contribution of the enzymatic activities of CD38 in the leukemic environment we took advantage of the Mec-1 cell line as a cellular model. This CLL-like cell line, constitutively CD38- and CD49d+ , was genetically modified by lentiviral infection to obtain CD38+ clones (CD38wt), as well as clones that express a mutant CD38 (mutation of glutamic acid at position 226 into aspartic acid, E226D, referred to as CD38M), which results in a complete loss of the enzymatic activities. Despite a similar molecular organization on the cell surface and the presence of an active signaling pathway upon engagement with agonistic mAbs, the two CD38 variants showed markedly different in vivo behaviors. This was shown by xenografting experiments into NOD/SCID/g chain-/- (NSG) mice: CD38wt cells were characterized by a higher growth rate and metastatic potential, which led to i) a significantly shorter survival as compared to both CD38M and CD38-negative cell lines (median survival of 30 days vs 36 days of CD38M vs 35.5 days of CD38 negative, p=0.0017 and p=0.0024 respectively), ii) a higher weight decrease of mice at day 28 (20% vs 8.45% vs 11.7%, p=0.026 and p=0.001 respectively) and iii) a more pronounced involvement of target organs, such as kidney, as highlighted by measuring organ volume by magnetic resonance imaging (477 mm3vs 294 mm3vs 300 mm3, p=0.028), or by checking for the presence of Mec-1 cells by IHC (19.12 vs 3.89% vs 2.14% of CD20+ area, p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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