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Open AccessArticle

Dissecting the Prognostic Significance and Functional Role of Progranulin in Chronic Lymphocytic Leukemia

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Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway
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Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Internal Medicine III, University of Ulm, 89081 Ulm, Germany
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Cooperation Unit Mechanisms of Leukemogenesis, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden–Württemberg–Hessen, 68167 Mannheim, Germany
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Internal Medicine III, University of Ulm, 89081 Ulm, Germany
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Department of Internal Medicine I, Saarland University, 66421 Homburg, Germany
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German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Authors to whom correspondence should be addressed.
Cancers 2019, 11(6), 822; https://doi.org/10.3390/cancers11060822
Received: 3 April 2019 / Revised: 30 May 2019 / Accepted: 5 June 2019 / Published: 13 June 2019
(This article belongs to the Special Issue Signaling Pathways and Immune Checkpoint Regulation in Cancer)
Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progression and death. This raised the question of whether GRN is a functional driver of CLL. We observed that recombinant GRN did not directly affect viability, activation, or proliferation of primary CLL cells in vitro. However, GRN secretion was induced in co-cultures of CLL cells with stromal cells that enhanced CLL cell survival. Gene expression profiling and protein analyses revealed that primary mesenchymal stromal cells (MSCs) in co-culture with CLL cells acquire a cancer-associated fibroblast-like phenotype. Despite its upregulation in the co-cultures, GRN treatment of MSCs did not mimic this effect. To test the relevance of GRN for CLL in vivo, we made use of the Eμ-TCL1 CLL mouse model. As we detected strong GRN expression in myeloid cells, we performed adoptive transfer of Eμ-TCL1 leukemia cells to bone marrow chimeric Grn−/− mice that lack GRN in hematopoietic cells. Thereby, we observed that CLL-like disease developed comparable in Grn−/− chimeras and respective control mice. In conclusion, serum GRN is found to be strongly upregulated in CLL, which indicates potential use as a prognostic marker, but there is no evidence that elevated GRN functionally drives the disease. View Full-Text
Keywords: chronic lymphocytic leukemia; tumor microenvironment; progranulin; prognostic serum marker; cancer-associated fibroblasts chronic lymphocytic leukemia; tumor microenvironment; progranulin; prognostic serum marker; cancer-associated fibroblasts
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Schulze-Edinghausen, L.; Dürr, C.; Öztürk, S.; Zucknick, M.; Benner, A.; Kalter, V.; Ohl, S.; Close, V.; Wuchter, P.; Stilgenbauer, S.; Lichter, P.; Seiffert, M. Dissecting the Prognostic Significance and Functional Role of Progranulin in Chronic Lymphocytic Leukemia. Cancers 2019, 11, 822.

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