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.
Highlights
Chronic lymphocytic leukemia (CLL) is characterized by the outgrowth of malignant CD5+ B cells and their increased detection in patients’ blood [1]
The crucial relevance of the CLL microenvironment is demonstrated by high apoptosis rates of CLL cells when they are cultured in vitro, which can be prevented by co-cultures with myeloid or non-hematopoietic stromal cells mimicking microenvironmental niches [15,16,17,18,19,20]
To evaluate the prognostic significance of progranulin (GRN) in CLL patients with advanced stage of disease, GRN was quantified in the serum of 249 patients included in the CLL8 study cohort (ClinicalTrials.gov: NCT00281918) and 42 age- and sex-matched healthy controls
Summary
Chronic lymphocytic leukemia (CLL) is characterized by the outgrowth of malignant CD5+ B cells and their increased detection in patients’ blood [1]. In contrast to chronic myeloid leukemia, CLL is not driven by a single deregulated pathway but diverse somatic mutations that affect various cellular processes have been detected in relatively low frequencies each [9,10,11]. It is widely accepted, that in addition to cell-intrinsic features the tumor microenvironment plays a substantial role in CLL pathogenesis. That fractions of proliferating CLL cells locate to tissue compartments where they interact with diverse accessory cells [12,13,14]. Targeting myeloid cells [21,23]
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