Abstract
B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL. NTSR2 was highly expressed in B-CLL cells, whereas expression of its natural ligand, neurotensin (NTS), was minimal in both B-CLL cells and patient plasma. Surprisingly, NTSR2 remained in a constitutively active phosphorylated state, caused not by a mutation-induced gain-of-function but rather by an interaction with the oncogenic tyrosine kinase receptor TrkB. Functional and biochemical characterization revealed that the NTSR2–TrkB interaction acts as a conditional oncogenic driver requiring the TrkB ligand brain-derived neurotrophic factor (BDNF), which unlike NTS is highly expressed in B-CLL cells. Together, NTSR2, TrkB and BDNF induce autocrine and/or paracrine survival pathways that are independent of mutation status and indolent or progressive disease course. The NTSR2–TrkB interaction activates survival signaling pathways, including the Src and AKT kinase pathways, as well as expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. When NTSR2 was downregulated, TrkB failed to protect B-CLL cells from a drastic decrease in viability via typical apoptotic cell death, reflected by DNA fragmentation and Annexin V presentation. Together, our findings demonstrate that the NTSR2–TrkB interaction plays a crucial role in B-CLL cell survival, suggesting that inhibition of NTSR2 represents a promising targeted strategy for treating B-CLL malignancy.
Highlights
Resistance to cell death is often associated with replicative immortality and chemotherapy evasion, two central hallmarks of cancer
Based on our previous observation that neurotensin receptors (NTSRs) are differentially expressed in malignant human B lymphocytes and drive resistance to Fas ligand-mediated cell death, we speculated that NTSRs contribute to apoptosis resistance in B-cell chronic lymphocytic leukemia (B-CLL) pathogenesis
Several studies have reported various mechanisms associated with B-CLL cell survival, many of which are related to B-cell receptor (BCR) activation, despite encouraging results using kinase inhibitors targeting the BCR pathway,[30] the frequency of resistance to this treatment and relapse in CLL patients highlights the deficiencies of current treatment protocols and suggests that other mechanisms are involved in CLL pathogenesis
Summary
Resistance to cell death is often associated with replicative immortality and chemotherapy evasion, two central hallmarks of cancer. This feature is prominent in B-cell chronic lymphocytic leukemia (B-CLL),[1] in which it leads to the accumulation of malignant mature B lymphocytes.[2] Several factors have been implicated in CLL development, including mutations in the immunoglobulin heavy-chain variable region gene (IGHV) and genomic alterations (deletion, translocation, trisomy and nonsynonymous mutations) used as prognostic markers for indolent or aggressive disease course.[3] Despite these molecular and genetic findings, no curative molecules that can definitively eradicate apoptosis-resistant B-CLL are yet available. GPCRs coupled to heterotrimeric G proteins, notably Giαs, regulate multiple immune functions and engage in cross-talk with other signaling pathways, including those mediated by tyrosine kinase receptors (TKRs)[5,6] such as the Src family of protein kinases (SRC)
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