Abstract
Chronic myeloid leukemia (CML) is caused by the fusion of the BCR activator of RhoGEF and GTPase activating protein (BCR) and ABL proto-oncogene, the nonreceptor tyrosine kinase (ABL) genes. Although the tyrosine kinase inhibitors (TKIs) imatinib (IM) and nilotinib (NI) have remarkable efficacy in managing CML, the malignancies in some patients become TKI-resistant. Here, we isolated bone marrow (BM)-derived mesenchymal stem cells (MSCs) from several CML patients by Ficoll-Hypaque density-gradient centrifugation for coculture with K562 and BV173 cells with or without TKIs. We used real-time quantitative PCR to assess the level of interleukin 7 (IL-7) expression in the MSCs and employed immunoblotting to monitor protein expression in the BCR/ABL, phosphatidylinositol 3-kinase (PI3K)/AKT, and JAK/STAT signaling pathways. We also used a xenograft tumor model to examine the in vivo effect of different MSCs on CML cells. MSCs from patients with IM-resistant CML protected K562 and BV173 cells against IM- or NI-induced cell death, and this protection was due to increased IL-7 secretion from the MSCs. Moreover, IL-7 levels in the BM of patients with IM-resistant CML were significantly higher than in healthy donors or IM-sensitive CML patients. IL-7 elicited IM and NI resistance via BCR/ABL-independent activation of JAK1/STAT5 signaling, but not of JAK3/STAT5 or PI3K/AKT signaling. IL-7 or JAK1 gene knockdown abrogated IL-7-mediated STAT5 phosphorylation and IM resistance in vitro and in vivo Because high IL-7 levels in the BM mediate TKI resistance via BCR/ABL-independent activation of JAK1/STAT5 signaling, combining TKIs with IL-7/JAK1/STAT5 inhibition may have significant utility for managing CML.
Highlights
Chronic myeloid leukemia (CML) is caused by the fusion of the BCR activator of RhoGEF and GTPase activating protein (BCR) and ABL proto-oncogene, the nonreceptor tyrosine kinase (ABL) genes
When cells were treated with interleukin 7 (IL-7) antibody and STAT5 inhibitor simultaneously, viability of K562 cells was significantly decreased (Fig. 5D), the results showed that the phosphatidylinositol 3-kinase (PI3K)/ AKT signaling pathway was not involved (Fig. 5C)
The BCR/ABL kinase inhibitors (BCR/ABL-KIs) imatinib, nilotinib, and dasatinib have proved to be effective in many CML patients [26], ; these tyrosine kinase inhibitors (TKIs) provide only transient anti-leukemia effects in Phϩ CML patients
Summary
The Key Laboratory of Hematology of Jiangxi Province, The Second Affiliated Hospital to Nanchang University, Nanchang University, Nanchang 330006, China. Association of BCR/ABL kinase mutations with tyrosine kinase inhibitor (TKI) resistance has been frequently reported (10 –14). Hematologic or cytogenetic response to NI was not dependent on whether kinase mutations exited in IM-resistant CML patients. These results imply that BCR/ABL-independent mechanisms may lead to TKI resistance during progression of the disease. We were prompted to address the potential MSC-derived cytokines that are involved in resistance to BCR/ABL inhibitors in CML.
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