title: K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors.
abstract: To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-Ras(G12D) murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to gamma-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Boston, MA, USA. thomas.kindler@ukmainz.de .
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Claudia
authors.initials: C
authors.lastname: Scholl
authors.forename: Jianing
authors.initials: J
authors.lastname: Liu
authors.forename: Dena S
authors.initials: DS
authors.lastname: Leeman
authors.forename: J Erika
authors.initials: JE
authors.lastname: Haydu
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D011905:Genes, ras; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D015458:Leukemia, T-Cell / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051881:Receptor, Notch1 / Q000235:genetics*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D018960:Hyaluronan Receptors; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases; D018631:ras Proteins