Abstract
SPARC is an extracellular matrix protein that exerts pleiotropic effects on extracellular matrix organization, growth factor availability, cell adhesion, differentiation, and immunity in cancer. Chronic myelogenous leukemia (CML) cells resistant to the BCR-ABL inhibitor imatinib (IM-R cells) were found to overexpress SPARC mRNA. In this study, we show that imatinib triggers SPARC accumulation in a variety of tyrosine kinase inhibitor (TKI)-resistant CML cell lines. SPARC silencing in IM-R cells restored imatinib sensitivity, whereas enforced SPARC expression in imatinib-sensitive cells promoted viability as well as protection against imatinib-mediated apoptosis. Notably, we found that the protective effect of SPARC required intracellular retention inside cells. Accordingly, SPARC was not secreted into the culture medium of IM-R cells. Increased SPARC expression was intimately linked to persistent activation of the Fyn/ERK kinase signaling axis. Pharmacologic inhibition of this pathway or siRNA-mediated knockdown of Fyn kinase resensitized IM-R cells to imatinib. In support of our findings, increased levels of SPARC mRNA were documented in blood cells from CML patients after 1 year of imatinib therapy compared with initial diagnosis. Taken together, our results highlight an important role for the Fyn/ERK signaling pathway in imatinib-resistant cells that is driven by accumulation of intracellular SPARC.
Highlights
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease due to the t(9; 22) translocation that encodes p210BCR-ABL [1], which activates several signaling pathways including ERK and Src kinases [2, 3]
SPARC expression was further increased by imatinib in IM-R K562 and LAMA-R cells (Fig. 1A)
Searching for genes modulated in IM-S versus IM-R cells led us to the identification of SPARC mRNA upregulation
Summary
Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease due to the t(9; 22) translocation that encodes p210BCR-ABL [1], which activates several signaling pathways including ERK and Src kinases [2, 3]. Imatinib is the first line treatment option for patients with CML and has proven efficacy in all stages of the disease [4, 5]. Resistance to imatinib occurs in all phases of the disease and second-generation inhibitors, such as dasatinib [6, 7] and nilotinib [8], have been developed to circumvent these. Authors' Affiliations: 1Universite de Nice Sophia Antipolis; INSERM U895, 2Team 1, and 3Team 2, 5INSERM U576, and 7Service d’Hematologie Clinique et Transplantation, Hôpital de l’Archet; 4Equipe labellisee par la Ligue Nationale Contre le Cancer; 6INSERM U876, Team Hematopoiesis, Universite Victor Segalen, CHU de Bordeaux; and 8Service d’Oncohematologie, CHU de Nice, Hôpital Pasteur, Nice, France. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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