Tumor Necrosis Factor-Alpha/Tumor Necrosis Factor-Alpha Receptor 1 Signaling Pathway Leads to Thymocytes' Cell Death by Necroptosis in a Mouse Model of Acute Myeloid Leukemia.

Abstract

Acute myeloid leukemia (AML) is characterized by an increased proliferation and loss of differentiation of hematopoietic myeloid progenitors or precursors. Studies performed in AML-affected patients revealed a T cell deficiency characterized by a reduced thymic output and peripheral functional abnormalities. To assess for the thymus function during AML, we used an AML mouse model and showed a drastic thymic atrophy. We observed a massive loss among double (CD4+CD8+- DP) and single positive (CD4+/8+- SP) thymocytes. We assessed for the expression of different actors of cell death signalling pathways by RT-qPCR or Western blotting. When comparing leukemic to control mice, there was a significant increase in the expression of Mlkl gene, phosphorylated MLKL and RIPK3 proteins, and tumor necrosis factor (TNF)-alpha receptors 1 on DP and SP thymocytes. These findings revealed a necroptosis cell death which was also observed in vitro when using cultured wild-type thymocytes and recombinant TNF-alpha protein. Thus, we demonstrated that TNF-alpha plays a deleterious role in thymic function during AML by contributing to extensive thymocytes' death.