title: ILK Induction in Lymphoid Organs by a TNFα-NF-κB-Regulated Pathway Promotes the Development of Chronic Lymphocytic Leukemia.
abstract: The proliferation of chronic lymphocytic leukemia (CLL) cells requires communication with the lymphoid organ microenvironment. Integrin-linked kinase (ILK) is a multifunctional intracellular adaptor protein that transmits extracellular signals to regulate malignant cell motility, metastasis, and cell-cycle progression, but is poorly characterized in hematologic malignancies. In this study, we investigated the role of ILK in the context of CLL and observed high ILK expression in patient samples, particularly in tumor cells harboring prognostic high-risk markers such as unmutated IGHV genes, high Zap70, or CD38 expression, or a signature of recent proliferation. We also found increased numbers of Ki67 (MKI67)-positive cells in regions of enhanced ILK expression in lymph nodes from CLL patients. Using coculture conditions mimicking the proliferative lymph node microenvironment, we detected a parallel induction of ILK and cyclin D1 (CCND1) expression in CLL cells that was dependent on the activation of NF-κB signaling by soluble TNFα. The newly synthesized ILK protein colocalized to centrosomal structures and was required for correct centrosome clustering and mitotic spindle organization. Furthermore, we established a mouse model of CLL in which B-cell-specific genetic ablation of ILK resulted in decelerated leukemia development due to reduced organ infiltration and proliferation of CLL cells. Collectively, our findings describe a TNFα-NF-κB-mediated mechanism by which ILK expression is induced in the lymph node microenvironment and propose that ILK promotes leukemogenesis by enabling CLL cells to cope with centrosomal defects acquired during malignant transformation. Cancer Res; 76(8); 2186-96. ©2016 AACR.
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Krenn
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Sebastian W
authors.initials: SW
authors.lastname: Hofbauer
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Pucher
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Hutterer
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hinterseer
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Denk
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Asslaber
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ganghammer
authors.affiliation: Department of Molecular Biology, Division of Molecular Tumor Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Sternberg
authors.affiliation: Institute of Pathology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.affiliation: Department of Molecular Biology, Division of Molecular Tumor Biology, University of Salzburg, Salzburg, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Aberger
authors.affiliation: Paul Gerson Unna Group 'Skin Homeostasis and Ageing,' Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Wickström
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Egle
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: Third Medical Department with Hematology, Medical Oncology, Hemostaseology, Infectious Diseases, and Rheumatology, Laboratory for Immunological and Molecular Cancer Research, Oncologic Center, Paracelsus Medical University, Salzburg, Austria. Salzburg Cancer Research Institute, Salzburg, Austria. t.hartmann@salk.at.
authors.forename: Tanja N
authors.initials: TN
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D008221:Lymphoid Tissue / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099200:Scaffold Protein ILK
chemical_list: D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099200:Scaffold Protein ILK