High IL-7 levels in the bone marrow microenvironment mediate imatinib resistance and predict disease progression in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is a three-stage myeloproliferative disease caused by translocation between chromosomes 9 and 22. Although tyrosine kinase inhibitors (TKI) are highly effective in the treatment of CML, numerous clinical trials have shown that many patients become refractory or drug resistance, especially those in the blastic crisis of CML. The molecular mechanisms underlying CML, however, remain poorly understood. In the present study, we used a coculture model to address possible mechanisms underlying the involvement of bone marrow microenvironment in the drug resistance of CML. Our data show that interleukin-7(IL-7) levels in the bone marrow of CML patients in blastic crisis are significantly higher than those of both healthy persons and CML patients in chronic and accelerated phases. The increased IL-7 was secreted by mesenchymal stem cells (MSC) in the bone marrow, which may protect leukemic cells from apoptosis induced by imatinib through JAK1/STAT5 signaling pathway. Our findings suggest that therapeutic strategies IL-7 signaling pathway may represent a promising approach for improving CML therapy, especially for patients in blastic crisis.

Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment

“…However, recent evidence shows that IL-7 promotes DNA synthesis in leukemia cells. Zhang and colleagues [169] identified a source of IL-7 in MSCs that secretes high levels of this cytokine to protect leukemic cells against apoptosis induced by Imatinib or Gleevec, a potent tyrosine kinase inhibitor. Of particular interest was another report showing that fatty acids produced by MSCs help cancer cells to survive after platinum-based chemotherapy (Cisplatin) [170].…”

“…MSCs' contribution to cancer survival is very similar to their role in tissue regeneration and maintenance of normal SCs niches [136, 173]. Among other cancer survival strategies, the TME promotes the generation of CSCs which in turn can actively educate their surroundings through interactions with other SCs (like MSCs) to guarantee self-renewal states and to give rise to the subsequent production of aggressive cells [169, 174]. Thus, MSCs' stemness-related properties, plasticity, and the ability to sustain tissue repair should be further studied in order to effectively target their cancer-supporting pathways in the TME.…”

“…CAIX regulates cellular pH while simultaneously promoting cancer cell survival and invasion [177]. Blocking the downstream activation of proteins induced by hypoxia (like ALKBH5, CAIX, and NANOG) has been shown to inhibit CSC expansion in the tumor site, decreasing the probabilities for tumor relapse after therapy [169, 174, 177]. …”

Early Predictors of Suboptimal Response to CML Therapy Could Help in Determining Treatment Strategy

“…These drugs have potent anti-proliferative effect, potentiate TKI effect, reducing adhesion of neoplastic cells to BM stroma and increasing apoptotic ability, on the long run there was a noticed decrease in prevalence of IM resistance and achieving optimal molecular response in previously resistant patients. 24,25 Our current study could suggest that addition of drugs that antagonize IL-7 may aid in modifying disease progression and help in cases resistant to IM therapy. This could be confirmed by data from Zhang and his colleagues, who reported that high IL-7 in bone marrow mediates imatinib resistance, and targeting IL-7 pathway is a promising approach in CML therapy.…”

Cysteine‐rich protein 61 regulates the chemosensitivity of chronic myeloid leukemia to imatinib mesylate through the nuclear factor kappa B/Bcl‐2 pathway

“…The chemoprotective effect of the BM microenvironment has been shown using in vitro CML cellular models under IM treatment . For example, cytokines within the BM microenvironment, such as interleukin (IL)‐3, IL‐7, granulocyte‐macrophage colony‐stimulating factor, and C‐X‐C motif chemokine 12, can protect CML cells from IM‐induced apoptosis and promote CML cell survival . However, it remains unknown whether there are other soluble factors that are chemoprotective for CML cells under IM treatment.…”