CD38/NAD + glycohydrolase and associated antigens in chronic lymphocytic leukaemia: from interconnected signalling pathways to therapeutic strategies
Abstract
Chronic lymphocytic leukaemia (CLL) is a heterogenous disease characterized by the accumulation of
neoplastic CD5+/CD19+ B lymphocytes. The spreading of the leukaemia relies on the CLL cell’s
ability to survive in the blood and migrate to and proliferate within the bone marrow and lymphoid
tissues. Some patients with CLL are either refractory to the currently available therapies or relapse
after treatment; this emphasizes the need for novel therapeutic strategies that improving clinical
responses and overcome drug resistance. CD38 is a marker of a poor prognosis and governs a set of
survival, proliferation and migration signals that contribute to the pathophysiology of CLL. The
literature data evidence a spatiotemporal association between the cell surface expression of CD38 and
that of other CLL antigens, such as the B-cell receptor (BCR), CD19, CD26, CD44, the integrin very
late antigen 4 (VLA4), the chemokine receptor CXCR4, the vascular endothelial growth factor
receptor-2 (VEGF-R2), and the neutrophil gelatinase-associated lipocalin receptor (NGAL-R). Most
of these proteins contribute to CLL cell survival, proliferation and trafficking, and cooperate with
CD38 in multilayered signal transduction processes. In general, these antigens have already been
validated as therapeutic targets in cancer, and a broad repertoire of specific monoclonal antibodies and
derivatives are available. Here, we review the state of the art in this field and examine the therapeutic
opportunities for cotargeting CD38 and its partners in CLL, e.g. by designing novel bi-/trispecific
antibodies.