title: Notch1 gene mutations target KRAS G12D-expressing CD8+ cells and contribute to their leukemogenic transformation.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meline
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D011289:Preleukemia / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051881:Receptor, Notch1; D051153:Wnt Proteins; D051176:beta Catenin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; Leukemia; Leukemia-initiating Cells; Lymphoma; Notch; Oncogene; Wnt Pathway