Increased Th17 cells and IL-17A exist in patients with B cell acute lymphoblastic leukemia and promote proliferation and resistance to daunorubicin through activation of Akt signaling

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.

Therapeutic Targeting of mTOR in T-Cell Acute Lymphoblastic Leukemia: An Update

“…Therefore, the use of mTOR inhibitors could further blunt immunological responses against leukemic cells. However, another recent report demonstrated that an Akt inhibitor counteracted Th17 cell-induced resistance to daunorubicin in a preclinical model of B-ALL [ 181 ].…”

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

“…We could identify 94 gene products and 47 molecular pathways that had close to 1 AUC scores for the ALL-normal comparison (Supplementary dataset S4, Table 1). Among those, branches of Akt signaling [24], cAMP [25], cytoplasmic and mitochondrial apoptosis [26], PTEN [27], ATM checkpoint [28], Hedgehog [29], HGF [30], GSK3 [31], Estrogen and Glucocorticoid reception [32, 33], IGF1R [34], IL2 [35], TNF [36], ILK [37], JAK-STAT [38], JNK [39], mTOR [40], TGF-beta [41], Ras [42], PPAR [43], NGF [44], VEGF [45], Wnt [46], HIF1 and Notch signaling [47] were previously reported in the literature as ALL-associated pathways. However, the identified GPCR and TRAF-associated apoptosis marker pathways were new, thus representing ~4% of the total ALL-specific pathways.…”

Malignant Interaction between B Cells and T Helper Cells

“…T h cell-derived cytokines can act on BCP-ALL cells as well, albeit with diverse effects. IL-2, IL-17 and IL-21, e.g., have been found to stimulate proliferation [83,93], while IL-4 and IL-13 inhibited BCP-ALL cell growth [88,[94][95][96], and IL-4 as well as TGF-β-induced apoptosis [97,98]. Cell-cell contact of BCP-ALL cells and activated allogenic T h cells induced activation and maturation of BCP-ALL cells [99].…”