Comment on Deaglio et al, page 3042
Deaglio and colleagues in this issue of Blood provide an important series of investigations that establish that CD38 expression is not simply a prognostic factor unrelated to the biology of CLL that correlates rapid disease progression, poor response to therapy, and inferior survival but rather is directly involved in the pathogenesis of this disease.
Previous work by many groups has demonstrated that chronic lymphocytic leukemia (CLL) cell contact with bone marrow stromal cells and nurselike cells inhibits apoptosis and provides an environment ideal for tumor proliferation and survival. Concurrent with this, a multitude of investigators have demonstrated that CD38 expression on CLL cells is commonly associated with both adverse clinical features, including rapid time from diagnosis to progression requiring treatment and poor response to therapy, and inferior overall survival. Additionally, CD38 expression has been correlated with heavy-chain variable region (VH) mutational status by some but not all investigators. To date, the absence of a link between CD38 expression in the pathogenesis of CLL and failure to demonstrate its independence from other prognostic factors such as VH mutational status, interphase cytogenetics, and p53 dysfunction has somewhat dampened enthusiasm for mechanistically pursuing CD38. Even more attention will certainly fall onto this potentially important cell surface antigen with the publication by Deaglio and colleagues in this issue of Blood.
Herein, Deaglio and colleagues describe a series of well-designed experiments demonstrating that CD38 ligation by an agonistic antibody or its natural ligand, CD31, mediates survival and proliferation in primary CLL cells. Additionally, these authors demonstrate that CD38 ligation also promotes increased expression of CD100 and diminished expression of CD100 low-affinity ligand CD72. Subsequent concurrent ligation of CD100 by its high-affinity ligand, plexin-B1, and of CD38 by a CD38 agonist antibody in these studies demonstrated synergistic protection from apoptosis. In vitro, these studies collectively suggest that the important cross-talk between CD38/CD31 and CD100/plexin-B1 results in both increased proliferation and diminished apoptosis, both features common to more aggressive CLL.
These findings are generated in vitro with reagents that are of questionable relevance to what is observed in vivo in CLL patients. What ties this artificially generated system to clinical relevance is the observation that CLL nurselike cells generated from patients express both CD31 and plexin-B1. Furthermore, coculture of CLL cells with antibodies that block CD38/CD31 and CD100/plexin-B1 interactions results in partial diminishment of the survival advantage provided by nurselike cells. Nurselike cells have been well described by others and are likely very important to providing CLL cells with survival signals in vivo. While these findings are potentially of great importance to our understanding another important piece of the pathogenesis driving high-risk CLL, further work will be required in a larger number of CLL samples to ascertain if this finding occurs in different genetic subsets of CLL and how other factors such as zeta-associated protein 70 (ZAP-70) overexpression contribute to this process. Nonetheless, this observation provides partial validation for therapeutic strategies to block this interaction in vivo through targeted antibody approaches or antagonizing the downstream signaling pathways following CD38 ligation. Indeed, while CD38 expression in CLL might not be a reliable biomarker for predicting VH mutational status, it does appear to be involved in the pathogenesis of the unfavorable biologic features associated with clinically aggressive and drug-resistant CLL. ▪
