Title:Multiple Metamorphoses of CD38 from Prognostic Marker to Disease Modifier to Therapeutic Target in Chronic Lymphocytic Leukemia
VOLUME: 13 ISSUE: 23
Author(s):Tiziana Vaisitti, Valentina Audrito, Sara Serra, Cinzia Bologna, Francesca Arruga, Davide Brusa, Roberta Buonincontri, Branimir Gizdic and Silvia Deaglio
Affiliation:Department of Medical Sciences, University of Turin School of Medicine & Human Genetics Foundation (HuGeF), via Nizza, 52, 10126 Torino, Italy.
Keywords:Chronic lymphocytic leukemia, CD38, ecto-enzymes, microenvironment, homing, therapeutic target.
Abstract:Human CD38, an ecto-enzyme and a receptor, performs as an independent negative prognostic marker for patients
with chronic lymphocytic leukemia (CLL), a hematological malignancy characterized by the accumulation of a
population of mature B lymphocytes expressing CD5. Patients with a CD38+ CLL clone display a more aggressive form
of the disease with earlier treatment requirements and ultimately shorter overall survival than patients with a CD38- clone.
Several lines of evidence indicate that CD38 is not only a diagnostic marker but also a key element in the molecular network
regulating disease maintenance and progression. First, CD38 is a receptor that induces proliferation and increases
survival of CLL cells. Second, CD38 signals facilitate access of CLL cells to growth-favorable districts. This is achieved
by enhancing i) chemotaxis towards CXCL12, ii) integrin-mediated adhesion and iii) matrix metalloprotease synthesis and
secretion. Third, blocking monoclonal antibodies targeting CD38 impair CLL homing to spleen and bone marrow in
xenograft models. These functions appear to be modulated by frontal interactions with CD31 as well as by lateral associations
on the CLL membrane to form a large supramolecular complex similar to the invadosomes of epithelial cells.
Our understanding has evolved from considering CD38 as a marker of unfavorable prognosis to recognizing its function
as a disease modifier. Studies in the next few years will likely determine whether the molecule can also serve as a target
for new therapies, using monoclonal antibodies, inhibitors of the enzymatic activity or both.
