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Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia.

ABSTRACT: Protective interactions with bystander cells in micro-environmental niches such as lymph nodes (LNs) contribute to survival and therapy resistance of chronic lymphocytic leukemia (CLL) cells. This is caused by a shift in expression of BCL-2 family members. Pro-survival proteins BCL-XL, BFL-1, and MCL-1 are upregulated by LN-residing T cells through CD40L interaction, presumably via NF-κB signaling. Macrophages also reside in the LN, and are assumed to provide important supportive functions for CLL cells. However, if and how macrophages are able to induce survival is incompletely known. We first established that macrophages induced survival due to an exclusive upregulation of MCL-1. Next, we investigated the mechanism underlying MCL-1 induction by macrophages in comparison with CD40L. Genome-wide expression profiling of in vitro macrophage- and CD40L-stimulated CLL cells indicated activation of the PI3K-AKT-mTOR pathway, which was confirmed in ex vivo CLL LN material. Inhibition of PI3K-AKT-mTOR signaling abrogated MCL-1 upregulation and survival by macrophages as well asCD40 stimulation. MCL-1 can be regulated at multiple levels, and we established that AKT leads to increased MCL-1 translation, but does not affect MCL-1 transcription or protein stabilization. Furthermore, among macrophage-secreted factors that could activate AKT, we found that induction of MCL-1 and survival critically depended on C-C Motif Chemokine Receptor-1 (CCR1). In conclusion, this study indicates that two distinct micro-environmental factors, CD40L and macrophages, signal via CCR1 to induce AKT activation resulting in translational stabilization of MCL-1, and hence can contribute to CLL cell survival.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94801 | GEO | 2017/02/11

SECONDARY ACCESSION(S): PRJNA374356

REPOSITORIES: GEO

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Project description:Amyloid light chain amyloidosis (AL) is an incurable protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains accumulate as amyloid fibrils in vital organs and cause multi-organ dysfunction that can be rapidly fatal. Current treatment regimens, which include proteasome inhibitors, were developed for the treatment of the more common plasma cell disease multiple myeloma and have demonstrated efficacy in AL amyloidosis. However, use of these agents is frequently limited due to multi-organ dysfunction at presentation, resulting in a median survival of 2-3 years and underscoring the need for novel therapies. By analyzing bone marrow-derived plasma cells from 44 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins that can potentially be targeted by recently-developed BH3 mimetics. In particular, we find that clonal plasma cells are highly dependent on the pro-survival MCL-1 and undergo apoptosis in response to single-agent treatment with an MCL-1 inhibitor. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, which is currently the standard of care for this disease, via the stabilization of Noxa and its direct inhibitory binding to MCL-1. BCL-2 inhibition with the FDA-approved inhibitor venetoclax (ABT-199) sensitizes plasma cells to bortezomib treatment and other front-line therapies, which can be observed in vitro and in vivo. Mass spectrometry-based proteomic analysis reveals changes in signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapy. Overall, our results indicate that BH3 mimetics may be highly effective therapies for AL amyloidosis that exploit inherent and induced dependencies on pro-survival proteins.

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Macrophages confer survival signals via CCR1-dependent translational MCL-1 induction in chronic lymphocytic leukemia.

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