Mechanism of IDH1-R132H mutation in T cell acute lymphoblastic leukemia mouse model via the Notch1 pathway

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a clonal malignant disease. Isocitrate Dehydrogenase 1-R123 (IDH1-R132 H) is related to T-ALL progression. This study explored the role of IDH1-R132H in T-ALL. Molt-4 cells with IDH1-R132H mutation were constructed by retroviral transfection of IDH1-R132H and T-ALL xenotransplantation mouse model was established by injection of Molt-4 cells through the tail vein. Infiltration of the liver, spleen, and bone marrow and the percentage of CD45-positive T-ALL cells in them were detected. Cell proliferation, apoptosis, and invasion were evaluated after the intervention of Notch1, PTEN, or PI3K expression. The leukocyte number was increased, the spleen was enlarged, infiltration in bone marrow, spleen, and liver tissue was worsened and the percentage of hCD45-positive T-ALL cells was increased by IDH1-R132H mutation, which promoted T-ALL deterioration. IDH1-R132H mutation promoted proliferation, invasion, and inhibited apoptosis of T-ALL cells, which were reversed by inhibition of Notch1. IDH1-R132H mutation upregulated HES1 expression and downregulated PTEN expression by activating the Notch1 pathway, while inhibition of Notch1 reversed these changes. PTEN inhibited the PI3K/AKT pathway activation. PTEN overexpression reversed IDH1-R132H mutation effect on promoting malignant behaviors of T-ALL cells. IDH1-R132H mutation inhibited PTEN expression by activating the Notch1/HES1 pathway, activated the PI3K/AKT pathway, thus promoting malignant behaviors of T-ALL cells.