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

Abstract

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.

Chronic lymphocytic leukemia cells impair osteoblastogenesis and promote osteoclastogenesis: role of TNFα, IL-6 and IL-11 cytokines

“…Moreover, a contribution of pSTAT3 and AKT, as downstream molecules involved in bone remodeling signals 31 by leukemic cells, may be envisaged through decreased levels of these molecules in BMSC treated with CLL-cm only, as compared with TNFα-neutralized CLL-cm. Interestingly, gene expression profile analysis of available in silico datasets 32 highlights that, in human mesenchymal stem cells (MSC), different molecules, involved in the regulation of osteoblast differentiation, become modulated after co-culture with CLL cells: a trend to a decrease in RUNX2 and significant decreases in the expression of collagen 1A, BMP-4 and BMP-6, along with increases in DKK-1 and osteopontin have been demonstrated ( Online Supplementary Figure S10 ). These observations further point to interactive crosstalk between CLL cells and MSC possibly leading to niche modifications.…”

Progranulin is essential for bone homeostasis and immunology

“…Meanwhile, PGRN supplementation to Sca1 + c‐Kit − hematopoietic bone marrow cells accelerates tumor formation 79 . PGRN expression is increased in chronic lymphocytic leukemia and breast cancer, which is related to disease prognosis 80,81 . In prostate cancer, prostate stem cell antigen plus PGRN promoted the adhesion of prostate cancer cells and bone marrow endothelial cells, thus facilitating bone metastases by activating the NF‐κB/integrin‐α4 pathways 82 …”

Age and Sex Differences in the Eμ-TCL1 Adoptive Transfer Mouse Model of CLL

“…In the last 4 years 32 papers reported Eµ-TCL1 adoptive transfer experiments. Most studies were performed using 6-12-week-old recipient mice with only 1 paper reported using mice older than 4 months [29]. Furthermore, of the 32 papers only 2 reported using male mice, but the data was not analyzed by sex.…”