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

Cancers

Axel Benner¹  Martina Seiffert²  Verena Kalter²  Peter Lichter²  Selcen Öztürk²  Lena Schulze-Edinghausen²  Claudia Dürr²  Sibylle Ohl²  Patrick Wuchter³  Viola Close⁴  Stephan Stilgenbauer⁴  Manuela Zucknick⁵ 

[1] Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden–Württemberg–Hessen, 68167 Mannheim, Germany;Internal Medicine III, University of Ulm, 89081 Ulm, Germany;Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0372 Oslo, Norway;

关键词: chronic lymphocytic leukemia;    tumor microenvironment;    progranulin;    prognostic serum marker;    cancer-associated fibroblasts;   

DOI  :  10.3390/cancers11060822

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown