Proliferative Signals in Chronic Lymphocytic Leukemia; What Are We Missing?

Chronic lymphocytic leukemia (CLL) cells cycle between lymphoid tissue sites where they actively proliferate, and the peripheral blood (PB) where they become quiescent. Strong evidence exists for a crucial role of B cell receptor (BCR) triggering, either by (self-)antigen or by receptor auto-engagement in the lymph node (LN) to drive CLL proliferation and provide adhesion. The clinical success of Bruton's tyrosine kinase (BTK) inhibitors is widely accepted to be based on blockade of the BCR signal. Additional signals in the LN that support CLL survival derive from surrounding cells, such as CD40L-presenting T helper cells, myeloid and stromal cells. It is not quite clear if and to what extent these non-BCR signals contribute to proliferation in situ. In vitro BCR triggering, in contrast, leads to low-level activation and does not result in cell division. Various combinations of non-BCR signals delivered via co-stimulatory receptors, Toll-like receptors (TLRs), and/or soluble cytokines are applied, leading to comparatively modest and short-lived CLL proliferation in vitro. Thus, an unresolved gap exists between the condition in the patient as we now understand it and applicable knowledge that can be harnessed in the laboratory for future therapeutic applications. Even in this era of targeted drugs, CLL remains largely incurable with frequent relapses and emergence of resistance. Therefore, we require better insight into all aspects of CLL growth and potential rewiring of signaling pathways. We aim here to provide an overview of in vivo versus in vitro signals involved in CLL proliferation, point out areas of missing knowledge and suggest future directions for research.