Bone marrow–derived mesenchymal stromal cells promote resistance to tyrosine kinase inhibitors in chronic myeloid leukemia via the IL-7/JAK1/STAT5 pathway

Abstract

Edited by Xiao-Fan Wang 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 realtime 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 IMresistant 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-7mediated 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.

The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment

“…The IL-7-mediated JAK1/STAT5 pathway bypasses BCR/ABL signals, protecting tumor cells from imatinib (IM) and nilotinib (NI) in a BCR/ABL-independent way. Interestingly this could explain the early resistance before the BCR/ABL genetic mutation (Zhang et al, 2019). IL-8, a neutrophil chemoattractant, is one of the CXC chemokine receptors 1 and 2 (CXCR1/2) ligands.…”

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

“…Differential methylation patterns have been shown to characterize the three phases of CML [ 190 ]. Downregulation of the pro-apoptotic BCL2-interacting mediator BIM by methylation is associated with reduced response to imatinib [ 191 ].…”

Acriflavine targets oncogenic STAT5 signaling in myeloid leukemia cells

“…16 Similarly, activation of STAT3 or STAT5 via a JAK-dependent but BCR-ABL-independent pathway promotes IM resistance of CML cells in BM microenvironment models. 28,37,38 Moreover, STAT5 has been shown to play a key role in the maintenance of LSCs from CML patients, whereas combining IM with a STAT5 inhibitor triggers the death of CML LSCs. 21 As a HIF inhibitor, ACF also targets CML LSCs while ACF combined with IM was more effective than IM alone in killing CML cells in low oxygen conditions.…”