Abstract 221P
Background
Acute myeloid leukemia (AML) is characterized by an increased proliferation of hematopoietic progenitors or precursors (blasts) of the different myeloid lineages. Studies performed in AML-affected patients revealed a T-cell immunodeficiency, characterized by a decreased number of peripheral T lymphocytes' TRECs and a restricted repertoire.
Methods
To study thymus dysfunction during AML, we used an AML mouse model in which we previously showed a thymic atrophy notably due to an increased cell death among double-positive (CD4+CD8+) thymocytes. To better understand this massive thymocytes’ loss, we collected ex vivo thymi from control and leukemic mice and immunophenotyped them for cell death. In parallel, we also assessed for the expression of different actors of cell death signaling pathways by RT-qPCR or Western Blotting.
Results
When comparing leukemic to control mice, there was a significant increase in the expression of Mlkl gene, phosphorylated MLKL and RIPK3 proteins and TNF-alpha receptors on double-positive (CD4+CD8+) thymocytes. These findings revealed an abnormal cell death of double-positive (CD4+CD8+) thymocytes by necroptosis (in addition to apoptosis) during AML. Such cell death was also observed in vitro using cultured wild-type thymocytes and recombinant TNF-alpha protein in the presence or absence of apoptosis inhibitors.
Conclusions
Thus, we demonstrated that TNF-alpha plays a deleterious role in thymic function during AML by contributing to extensive thymocytes’ loss. Further investigations will help to better characterize its impact on the peripheral T-cell repertoire and antigens recognition.
Legal entity responsible for the study
Meriem Ben Khoud, Nathalie Jouy, Bruno Quesnel and Carine Brinster.
Funding
Canther UMR 9020 CNRS UMR 1277 INSERM.
Disclosure
All authors have declared no conflicts of interest.