Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia.

Santos A Susin,Brigitte Bauvois,Elise Chapiro,Elodie Pramil,Claire Quiney,Karim Maloum,Florence Nguyen-Khac,Ludovic Jondreville

doi:10.3390/cancers12082124

Abstract

The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment.

Highlights

Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5+ B lymphocytes in the immune system [1]
We found that the serum level of free neutrophil gelatinase-associated lipocalin (NGAL) was significantly higher in the untreated CLL group than in the healthy group (Figure 1A)
We looked at whether NGAL influenced the balance between death and survival in CLL cells cells obtained from untreated patients

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease characterized by a peripheral accumulation of abnormal CD5+ B lymphocytes in the immune system [1]. The leukemic cells (which are mostly quiescent) mainly accumulate because they are unable to develop a cell death program—even though proliferating pools are found in the bone marrow and lymph nodes [1] This leads to the progressive failure of the patient’s immune and hematopoietic systems [1]. Novel signaling inhibitors targeting B cell receptor (BCR)-associated kinases (i.e., Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib) have recently been approved in the USA and Europe for relapsed CLL or untreated CLL bearing a TP53 abnormality [4,5]. Another alternative strategy involves targeting the B-cell lymphoma-2 (Bcl-2) anti-apoptotic protein, which is overexpressed in

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Conclusion