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1096 Activating NOTCH1 Mutations Alter T-ALL Chemosensitivity By PREX2-AKT Pathway

Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, Diseases, cell regulation, Biological Processes, Lymphoid Malignancies, pathways, signal transduction
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Hui Yu, M.D., Ph.D1*, Yuxin DU, M.D., M.S.1*, Ji Xu, M.D., Ph.D2*, Zhenchang Sun, M.D., Ph.D1*, Xiaorui Fu, M.D., Ph.D1*, Ken H. Young, M.D., Ph.D3 and Mingzhi Zhang, MD1*

1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
2School of Basic Medical Science, Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, zhengzhou, China
3Duke Medical Center and Duke Cancer institute, Duke University School of Medicine, Durham, NC

Mutations on NOTCH1 gene are the most commonly found mutations in T-cell acute lymphoblastic leukemia (T-ALL) and they are reported to be favorable indicators for T-ALL patients’ prognosis. However, the effects of activating NOTCH1 mutations on T-ALL’s chemosensitivity have not been studied. We reported that NOTCH1 inhibition by γ-secretase inhibitors or shRNA knockdown in MOLT-3 cells could reduce the T-ALL cells’ sensitivity to chemotherapeutic drugs. However, this effect was absent in Jurkat and CUTLL cells. We further demonstrated that NOTCH1 inhibition could activate the PI3K-AKT pathway in a cell specific pattern similar as their effects on chemosensitivity. RNA-seq revealed that Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 2 (PREX2) is a target gene of NOTCH1 and may mediate the effects of activating NOTCH1 mutations on chemosensitivity. Consistently, we proved that overexpression of PREX2 could mimic the effects of NOTCH1 inhibition on chemosensitivity. Our study has highlighted the effects of activating NOTCH1 mutations on T-ALL’s chemosensitivity by altering PREX2-AKT pathway, which may explain the favorable effects of NOTCH1 mutations on T-ALL patients’ prognosis, as well as provided potential targets to alter T-ALL cells’ chemosensitivity.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH