Abstract
BackgroundImmune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). It has been reported that Th17 cells as a newly identified subset of CD4+ T cells are involved in the pathogenesis of several hematological disorders. However, the role of Th17 cells in the pathophysiology of B-ALL is still unclear.MethodsThe frequencies of T cells were determined by flow cytometry in the peripheral blood and bone marrow of 44 newly diagnosed B-ALL patients and 25 age-matched healthy donors. The cell viability and apoptosis were determined by CCK-8 assay and Annexin V staining, respectively. Western blot was applied to identify the level of Akt and Stat3 phosphorylation.ResultsWe assessed and observed a significantly increased frequency of Th17 cells and a drastically decreased frequency of Th1 cells in peripheral blood mononuclear cells and bone marrow mononuclear cells from newly diagnosed B-ALL patients compared with healthy donors. Furthermore, increased levels of Th17-related cytokines including IL-17, IL-21, IL-23, IL-1β, and IL-6 were presented in between blood and marrow in B-ALL patients. Both IL-17A and IL-21, two Th17-secreted cytokines, induced the proliferation of B-ALL cell line Nalm-6 and patient B-ALL cells isolated from B-ALL patients, herein either cytokine led to the phosphorylation of Akt and Stat3. Additionally, IL-17A promoted resistance to daunorubicin via activation of Akt signaling and the PI3K/Akt inhibitor LY294002 or perifosine almost completely rescued daunorubicin-induced cell death in B-ALL cells.ConclusionsOur findings suggest that elevated Th17 cells secrete IL-17A by which promotes the proliferation and resistance to daunorubicin in B-ALL cells through activation of Akt signaling. Th17 cells may represent a novel target to improve B-ALL immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0894-9) contains supplementary material, which is available to authorized users.
Highlights
Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL)
To investigate whether Th17 cells are enriched in B-ALL, we evaluated the frequency of Th17 cells based on cytokine patterns after in vitro stimulation with phorbol 12-myristate13-acetate (PMA) plus ionomycin in short-term culture
We simultaneously analyzed the frequency of Th1 cells and found that the frequency of Th1 cells was significantly decreased in both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMMCs) from B-ALL patients compared with those from healthy donors (Fig. 1a and b)
Summary
Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). B-cell acute lymphoblastic leukemia (B-ALL) characterized by accumulation of immature lymphoid progenitors affects both children and adults. Pro-survival signals provided by tissue microenvironments, such as intricate crosstalk between B-ALL cells and CD4+ T cells, mesenchymal stromal cells, and various cytokines, contribute to maintain leukemic clones and promote resistance to chemotherapy in adult B-ALL patients [2]. Th17 cells, named for their signature production of IL-17A, secrete IL-17F, IL-21, and IL-22, thereby inducing an enormous tissue reaction due to the broad distribution of the IL-17 and IL-21 receptors and exerting a crucial role in the development of inflammatory and autoimmune diseases [3,4,5,6]. The immune system fails to identify and eliminate B-ALL cells, by which contributes to the development of B-ALL
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