2036 – INFLAMMAGING AND T-ALL: ONCOGENE-CYTOKINE INTERACTIONS AND THEIR ROLE IN LEUKEMOGENESIS

T-cell acute lymphoblastic leukemia (T-ALL) can affect any age group; however, disease outcome is worse in older patients. Aging has been described to be accompanied by an increase in the body's proinflammatory status, a phenomenon referred as “inflammaging”. By analysing two T-ALL transcriptome datasets, we have found that inflammation pathways are upregulated in older patients, whereas younger patients present upregulation of cell cycle pathways, suggesting that inflammaging is also recapitulated in T-ALL. Here, we hypothesize that T-ALL oncogenes can cooperate with specific cytokines/stimuli and their signaling pathways to create distinct leukemic phenotypes. To test this, human cord blood CD34+ cells were transduced with different T-ALL oncogenes and grown in co-culture with stromal cells under different pro-inflammatory conditions. We observed that most of the transduced cells had their cell growth negatively affected by the proinflammatory conditions, although some oncogene combinations showed more tolerance to these conditions than others. Activated NOTCH1+TLX3 transduced cells represented the only gene combination that showed significantly higher cell growth in the presence of interferon-gamma (IFNγ) when compared to non-transduced cells in the same culture. IL-15 and IFNγ potentiated differentiation arrest observed with certain oncogene combinations. Normal uncommitted T-cell progenitors (CD7+CD5+CD44+CD1a-) responded to IL-15 via STAT5 and AKT phosphorylation, and this response was enhanced by chronic treatment with IL-15. Our results suggest that proinflammatory conditions can alter the effect of certain oncogenes on T-cell progenitors and influence leukemogenesis, potentially leading to distinct biological behaviors of resulting leukemias. These findings may lead to identification of cytokine dependencies associated with particular T-ALL genetic subtypes.