Your browser doesn't support javascript.
loading
Quantitative phosphotyrosine profiling of patient-derived xenografts identifies therapeutic targets in pediatric leukemia.
Dolai, Sibasish; Sia, Keith C S; Robbins, Alissa K; Zhong, Ling; Heatley, Sue L; Vincent, Tiffaney L; Hochgräfe, Falko; Sutton, Rosemary; Kurmasheva, Raushan T; Revesz, Tamas; White, Deborah L; Houghton, Peter J; Smith, Malcolm A; Teachey, David T; Daly, Roger J; Raftery, Mark J; Lock, Richard B.
Afiliação
  • Dolai S; Leukemia Biology, Childrens Cancer Institute.
  • Sia KC; Leukaemia Biology, Children's Cancer Institute.
  • Robbins AK; Leukaemia Biology Program, Childrens Cancer Institute.
  • Zhong L; Mark Wainwright Analytical Centre, Bioanalytical Mass Spectrometry Facility.
  • Heatley SL; Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI).
  • Vincent TL; Divison of Oncology, Children's Hospital of Philadelphia.
  • Hochgräfe F; Competence Center Functional Genomics, University of Greifswald.
  • Sutton R; Leukaemia Biology, Children's Cancer Institute.
  • Kurmasheva RT; Molecular Medicine, UTHSC San Antonio.
  • Revesz T; Women's & Children's Hospital, SA Pathology.
  • White DL; Cancer Theme, SAHMRI.
  • Houghton PJ; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio.
  • Smith MA; Cancer Therapy Evaulation Program, National Cancer Institute.
  • Teachey DT; Oncology, Children's Hospital of Philadelphia.
  • Daly RJ; Department of Biochemistry and Molecular Biology, Monash University.
  • Raftery MJ; Bioanalytical Mass Spectrometry Facility, University of New South Wales.
  • Lock RB; Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW rlock@ccia.org.au.
Cancer Res ; 76(9): 2766-2777, 2016 05.
Article em En | MEDLINE | ID: mdl-26960974
Activating mutations in tyrosine kinases (TKs) drive pediatric high-risk acute lymphoblastic leukemia (ALL) and confer resistance to standard chemotherapy. Therefore, there is urgent need to characterize dysregulated TK signaling axes in patients with ALL and identify actionable kinase targets for the development of therapeutic strategies. Here, we present the first study to quantitatively profile TK activity in xenografted patient biopsies of high-risk pediatric ALL. We integrated a quantitative phosphotyrosine profiling method with 'spike-in' stable isotope labeling with amino acids in cell culture (SILAC) and quantified 1394 class I phosphorylation sites in 16 ALL xenografts. Moreover, hierarchical clustering of phosphotyrosine sites could accurately classify these leukemias into either B or T-cell lineages with the high-risk early T-cell precursor (ETP) and Ph-like ALL clustering as a distinct group. Furthermore, we validated this approach by using specific kinase pathway inhibitors to perturb ABL1, FLT3, and JAK TK signaling in four xenografted patient samples. By quantitatively assessing the tyrosine phosphorylation status of activated kinases in xenograft models of ALL, we were able to identify and validate clinically relevant targets. Therefore, this study highlights the application and potential of phosphotyrosine profiling for identifying clinically relevant kinase targets in leukemia.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2016 Tipo de documento: Article