TY - JOUR
T1 - Lenalidomide interferes with Tumor-Promoting properties of Nurse-Like cells in chronic lymphocytic leukemia
AU - Fiorcari, Stefania
AU - Martinelli, Silvia
AU - Bulgarelli, Jenny
AU - Audrito, Valentina
AU - Zucchini, Patrizia
AU - Colaci, Elisabetta
AU - Potenza, Leonardo
AU - Narni, Franco
AU - Luppi, Mario
AU - Deaglio, Silvia
AU - Marasca, Roberto
AU - Maffei, Rossana
N1 - Publisher Copyright:
©2015 Ferrata Storti Foundation.
PY - 2015
Y1 - 2015
N2 - Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lympho-cytic leukemia patients, nurse-like cells differentiate from CD14+ mononuclear cells and protect chronic lympho-cytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lym-phocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14+ monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues.
AB - Lenalidomide is an immunomodulatory agent clinically active in chronic lymphocytic leukemia patients. The specific mechanism of action is still undefined, but includes modulation of the microenvironment. In chronic lympho-cytic leukemia patients, nurse-like cells differentiate from CD14+ mononuclear cells and protect chronic lympho-cytic leukemia cells from apoptosis. Nurse-like cells resemble M2 macrophages with potent immunosuppressive functions. Here, we examined the effect of lenalidomide on the monocyte/macrophage population in chronic lym-phocytic leukemia patients. We found that lenalidomide induces high actin polymerization on CD14+ monocytes through activation of small GTPases, RhoA, Rac1 and Rap1 that correlated with increased adhesion and impaired monocyte migration in response to CCL2, CCL3 and CXCL12. We observed that lenalidomide increases the number of nurse-like cells that lost the ability to nurture chronic lymphocytic leukemia cells, acquired properties of phagocytosis and promoted T-cell proliferation. Gene expression signature, induced by lenalidomide in nurse-like cells, indicated a reduction of pivotal pro-survival signals for chronic lymphocytic leukemia, such as CCL2, IGF1, CXCL12, HGF1, and supported a modulation towards M1 phenotype with high IL2 and low IL10, IL8 and CD163. Our data provide new insights into the mechanism of action of lenalidomide that mediates a pro-inflammatory switch of nurse-like cells affecting the protective microenvironment generated by chronic lymphocytic leukemia into tissues.
UR - http://www.scopus.com/inward/record.url?scp=84964301380&partnerID=8YFLogxK
U2 - 10.3324/haematol.2014.113217
DO - 10.3324/haematol.2014.113217
M3 - Article
SN - 0390-6078
VL - 100
SP - 253
EP - 262
JO - Haematologica
JF - Haematologica
IS - 2
ER -