title: Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia.
abstract: Gain-of-function NOTCH1 mutations are found in 50%-70% of human T cell acute lymphoblastic leukemia/lymphoma (T-ALL) cases. Gain-of-function NOTCH1 alleles that initiate strong downstream signals induce leukemia in mice, but it is unknown whether the gain-of-function NOTCH1 mutations most commonly found in individuals with T-ALL generate downstream signals of sufficient strength to induce leukemia. We addressed this question by expressing human gain-of-function NOTCH1 alleles of varying strength in mouse hematopoietic precursors. Uncommon gain-of-function NOTCH1 alleles that initiated strong downstream signals drove ectopic T cell development and induced leukemia efficiently. In contrast, although gain-of-function alleles that initiated only weak downstream signals also induced ectopic T cell development, these more common alleles failed to efficiently initiate leukemia development. However, weak gain-of-function NOTCH1 alleles accelerated the onset of leukemia initiated by constitutively active K-ras and gave rise to tumors that were sensitive to Notch signaling pathway inhibition. These data show that induction of leukemia requires doses of Notch1 greater than those needed for T cell development and that most NOTCH1 mutations found in T-ALL cells do not generate signals of sufficient strength to initiate leukemia development. Furthermore, low, nonleukemogenic levels of Notch1 can complement other leukemogenic events, such as activation of K-ras. Even when Notch1 participates secondarily, the resulting tumors show "addiction" to Notch, providing a further rationale for evaluating Notch signaling pathway inhibitors in leukemia.
authors.affiliation: Division of Hematology-Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Mark Y
authors.initials: MY
authors.lastname: Chiang
authors.forename: Lanwei
authors.initials: L
authors.lastname: Xu
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.forename: Gavin
authors.initials: G
authors.lastname: Histen
authors.forename: Sarah
authors.initials: S
authors.lastname: L'heureux
authors.forename: Candice
authors.initials: C
authors.lastname: Romany
authors.forename: M Eden
authors.initials: ME
authors.lastname: Childs
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D015973:Gene Expression Regulation, Leukemic; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1