title: Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.
abstract: Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York 10032, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Sulis
authors.forename: Maria
authors.initials: M
authors.lastname: Cortina
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Real
authors.forename: Kelly
authors.initials: K
authors.lastname: Barnes
authors.forename: Maria
authors.initials: M
authors.lastname: Ciofani
authors.forename: Esther
authors.initials: E
authors.lastname: Caparros
authors.forename: Jean
authors.initials: J
authors.lastname: Buteau
authors.forename: Kristy
authors.initials: K
authors.lastname: Brown
authors.forename: Sherrie L
authors.initials: SL
authors.lastname: Perkins
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Archana M
authors.initials: AM
authors.lastname: Agarwal
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagase
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.forename: Maria
authors.initials: M
authors.lastname: Dominguez
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D029721:Drosophila Proteins; D051881:Receptor, Notch1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487101:PTEN protein, Drosophila; C494929:PTEN protein, human