title: 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 B-cell lymphoma 2 (BCL-2) family members. Pro-survival proteins B-cell lymphoma-extra large (BCL-XL), BCL-2-related protein A1 (BFL-1) and myeloid leukemia cell differentiation protein 1 (MCL-1) are upregulated by LN-residing T cells through CD40L interaction, presumably via nuclear factor (NF)-κB signaling. Macrophages (Mφs) also reside in the LN, and are assumed to provide important supportive functions for CLL cells. However, if and how Mφs are able to induce survival is incompletely known. We first established that Mφs induced survival because of an exclusive upregulation of MCL-1. Next, we investigated the mechanism underlying MCL-1 induction by Mφs in comparison with CD40L. Genome-wide expression profiling of in vitro Mφ- and CD40L-stimulated CLL cells indicated activation of the phosphoinositide 3-kinase (PI3K)-V-Akt murine thymoma viral oncogene homolog (AKT)-mammalian target of rapamycin (mTOR) pathway, which was confirmed in ex vivo CLL LN material. Inhibition of PI3K-AKT-mTOR signaling abrogated MCL-1 upregulation and survival by Mφs, as well as CD40 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 Mφ-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 Mφs, signal via CCR1 to induce AKT activation resulting in translational stabilization of MCL-1, and hence can contribute to CLL cell survival.
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M H A
authors.initials: MHA
authors.lastname: van Attekum
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Terpstra
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Slinger
authors.affiliation: Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: von Lindern
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: P D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Jongejan
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Kater
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D054389:Receptors, CCR1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054389:Receptors, CCR1; D023201:CD40 Ligand