Notch1 Gene Mutations Target KRAS G12D-expressing CD8+ Cells and Contribute to Their Leukemogenic Transformation

• Published in: The Journal of biological chemistry Vol. 288; no. 25; pp. 18219 - 18227
• Main Authors: Kong, Guangyao, Du, Juan, Liu, Yangang, Meline, Benjamin, Chang, Yuan-I, Ranheim, Erik A., Wang, Jinyong, Zhang, Jing
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adult; Animals; beta Catenin - metabolism; Bone Marrow Transplantation; CD8-Positive T-Lymphocytes - metabolism; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Flow Cytometry; Humans; Kaplan-Meier Estimate; KRAS; Leukemia; Leukemia-initiating Cells; Lymphoma; Mice; Mice, Inbred BALB C; Molecular Bases of Disease; Mutation; Notch; Oncogene; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - surgery; Preleukemia - genetics; Preleukemia - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal Transduction; Wnt Pathway; Wnt Proteins - metabolism; Leukemia-initiating Cells; Leukemia; Oncogene; Notch; KRAS; Wnt Pathway; Lymphoma
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.475376

Acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive hematopoietic malignancy affecting both children and adults. Previous studies of T-ALL mouse models induced by different genetic mutations have provided highly diverse results on the issues of T-cell leukemia/lymphoma-initiating cells (T-LICs) and potential mechanisms contributing to T-LIC transformation. Here, we show that oncogenic Kras (Kras G12D) expressed from its endogenous locus is a potent inducer of T-ALL even in a less sensitized BALB/c background. Notch1 mutations, including exon 34 mutations and recently characterized type 1 and 2 deletions, are detected in 100% of Kras G12D-induced T-ALL tumors. Although these mutations are not detected at the pre-leukemia stage, incremental up-regulation of NOTCH1 surface expression is observed at the pre-leukemia and leukemia stages. As secondary genetic hits in the Kras G12D model, Notch1 mutations target CD8+ T-cells but not hematopoietic stem cells to further promote T-ALL progression. Pre-leukemia T-cells without detectable Notch1 mutations do not induce T-ALL in secondary recipient mice compared with T-ALL tumor cells with Notch1 mutations. We found huge variations in T-LIC frequency and immunophenotypes of cells enriched for T-LICs. Unlike Pten deficiency-induced T-ALL, oncogenic Kras-initiated T-ALL is not associated with up-regulation of the Wnt/β-catenin pathway. Our results suggest that up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Notch1 mutations and Kras G12D contribute cooperatively to leukemogenic transformation of normal T-cells. Endogenous oncogenic Kras induces a highly penetrant acute T-cell lymphoblastic leukemia/lymphoma (T-ALL). Up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Notch1 mutations contribute to leukemogenic transformation of normal T-cells. Our data provide a rationale to target both NOTCH1 and RAS signaling for T-ALL treatment.