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CD38/NAD + glycohydrolase and associated antigens in chronic lymphocytic leukaemia: from interconnected signalling pathways to therapeutic strategies

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Bauvois, Brigitte | Nguyen-Khac, Florence | Merle-Béral, Hélène | Susin, Santos

Edité par CCSD ; Elsevier -

International audience. Chronic lymphocytic leukaemia (CLL) is a heterogenous disease characterized by the accumulation ofneoplastic CD5+/CD19+ B lymphocytes. The spreading of the leukaemia relies on the CLL cell’sability to survive in the blood and migrate to and proliferate within the bone marrow and lymphoidtissues. Some patients with CLL are either refractory to the currently available therapies or relapseafter treatment; this emphasizes the need for novel therapeutic strategies that improving clinicalresponses and overcome drug resistance. CD38 is a marker of a poor prognosis and governs a set ofsurvival, proliferation and migration signals that contribute to the pathophysiology of CLL. Theliterature data evidence a spatiotemporal association between the cell surface expression of CD38 andthat of other CLL antigens, such as the B-cell receptor (BCR), CD19, CD26, CD44, the integrin verylate antigen 4 (VLA4), the chemokine receptor CXCR4, the vascular endothelial growth factorreceptor-2 (VEGF-R2), and the neutrophil gelatinase-associated lipocalin receptor (NGAL-R). Mostof these proteins contribute to CLL cell survival, proliferation and trafficking, and cooperate withCD38 in multilayered signal transduction processes. In general, these antigens have already beenvalidated as therapeutic targets in cancer, and a broad repertoire of specific monoclonal antibodies andderivatives are available. Here, we review the state of the art in this field and examine the therapeuticopportunities for cotargeting CD38 and its partners in CLL, e.g. by designing novel bi-/trispecificantibodies.

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