CD38 at the junction between prognostic marker and therapeutic target Silvia Deaglio 1 , Semra Aydin 1 , Tiziana Vaisitti 1 , Luciana Bergui 2 and Fabio Malavasi 1 1 Laboratory of Immunogenetics, Department of Genetics, Biology and Biochemistry and CeRMS, Via Santena 19, 10126 Torino, Italy 2 Department of Medicine and Experimental Oncology, University of Torino School of Medicine, Via Santena 19, 10126 Torino, Italy CD38 is an ectoenzyme involved in transmembrane signaling and cell adhesion and is used as a disease marker for leukemias and myeloma. CD38 is a depend- able negative prognostic marker for chronic lymphocytic leukemia (CLL). Recent evidence indicates that CD38 is a component of a complex network delivering growth and survival signals to CLL cells. In conjunction with chemo- kines and their receptors, CD38 also influences cell migratory responses. These considerations are the rationale for devising a CLL therapy that uses CD38 as the target. The use of reagents specifically blocking the molecule might provide a new approach for interfering with deleterious growth circuits, therefore increasing the susceptibility of leukemic cells to conventional che- motherapy. Introduction CD38 is an ectoenzyme involved in transmembrane sig- naling and cell adhesion. It is useful as a disease marker for leukemias and myeloma, but it might also be relevant in the pathogenesis and evolution of chronic lymphocytic leukemia (CLL). This review presents the findings and considerations that support the use of CD38 as a potential therapeutic target for CLL. Human CD38 was originally designated as an activation marker during the quest to identify cell surface molecules involved in T cell recognition. This definition was later proven inadequate when the molecule was shown to be neither lineage- nor activation-restricted. Today, CD38 is defined as both as a cell surface enzyme (i.e., ectoenzyme) and as a receptor [1,2]. The concept of ectoenzyme is a recent acquisition in leukocyte biology, and the notion that surface enzymes can also function as receptors was initially received with skepticism. The phylogenic history of CD38 indicates that the molecule is derived almost unmodified in amino acid sequence from the sea mollusk Aplysia californica, where it is a soluble enzyme in the ovotestis. Over the course of its long evolutionary journey to mammals and Homo sapiens, CD38 maintained its enzymatic properties, while also acquiring membrane anchorage and becoming a cell surface receptor. Its distri- bution in humans is nearly ubiquitous in cells of the innate and acquired immune system as well as in other tissues, and it has variable levels of expression (Table 1). In humans, CD38 has been studied in models as disparate as pancreatic secretion, muscle contraction, lymphocyte activation and, more generally, as a marker of terminal cell differentiation in physiology and pathology. The mol- ecule has been investigated by using a wide variety of analytical tools, from pure enzymatic approaches to mono- clonal antibodies (mAbs), used either as agonistic or inhibi- tory reagents to influence the functions exerted by the molecule. Table 1 lists the main tissues and cells where CD38 is present. The functions attributed to the molecule are linked either to enzymatic or receptorial functions. The final outcome is dependent on the inter- actions with other ectoenzymes and/or signaling mol- ecules, which vary according to tissue and sub-cellular localization. Like many other CD molecules, CD38 was included in blind searches for disease markers. It is still of clinical value in the characterization of leukemias and myeloma, but CD38 has more recently been examined with an eye to whether its pleiotropic functions are also relevant in the pathogenesis and evolution of hematological malignancies. CLL represented an ideal model for the testing of this hypothesis. Shifting awareness from CD38 as a marker to CD38 as a disease modifier will not only be of benefit and satisfaction to basic scientists; it is likely to have a profound impact on our understanding of CD38 as a therapeutic target, possibly unraveling new and important details about the molecule. The first part of this review examines the physiology of CD38, touching briefly on its structure, distribution and functions. The second part reports on the involvement of CD38 in disease, focusing on its role in CLL. Observations from clinics are then reviewed in light of inferences stem- ming from knowledge of the molecule’s multiple functions, thus providing the rationale for potential therapeutic applications, which are presented in the final section. Biology of human CD38 Human CD38 is a type II surface glycoprotein expressed by immature hematopoietic cells, downregulated by mature cells and re-expressed at high levels by activated lympho- cytes such as T cells, B cells, dendritic cells and natural Review Corresponding authors: Deaglio, S. (silvia.deaglio@unito.it); Malavasi, F. (fabio.malavasi@unito.it). TRMOME-485; No of Pages 9 1471-4914/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2008.02.005 Available online xxxxxx 1