Kinase activity profiling reveals active signal transduction pathways in pediatric acute lymphoblastic leukemia: A new approach for target discovery

Naomi E. van der Sligte, Frank J. G. Scherpen, Tiny G. J. Meeuwsen-de Boer, Harm Jan Lourens, Arja ter Elst, Sander H. Diks, Victor Guryev, Maikel P. Peppelenbosch, Frank N. van Leeuwen, Eveline S. J. M. de Bont*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

Abstract

Still about 20% of patients with acute lymphoblastic leukemia (ALL) struggle with relapse, despite intensive chemotherapy. We and others have shown that kinase activity profiling is able to give more insights in active signal transduction pathways and point out interesting signaling hubs as well as new potential druggable targets. With this technique the gap between newly designed drugs and ALL may be bridged. The aim of this study was to perform kinome profiling on 20 pediatric ALL samples (14 BCP-ALL and six T-ALL) to identify signaling proteins relevant to ALL. We defined 250 peptides commonly activated in both BCP-ALL and T-ALL representing major signal transduction pathways including MAPK, PI3K/Akt, and regulators of the cell cycle/p53 pathway. For 27 peptides, differentially phosphorylation between BCP-ALL and T-ALL was observed. Among these, ten peptides were more highly phosphorylated in BCP-ALL while 17 peptides showed increased phosphorylation in T-ALL. Furthermore we selected one lead of the list of commonly activated peptides (HGFR_Y1235) in order to test its efficacy as a potential target and provide proof of principle for this approach. In conclusion kinome profiling is an elegant approach to study active signaling and identify interesting potential druggable targets.

Original languageEnglish
Pages (from-to)1245-1254
Number of pages10
JournalProteomics
Volume15
Issue number7
DOIs
Publication statusPublished - Apr-2015

Keywords

  • Acute lymphoblastic leukemia
  • HGFR
  • Kinome profiling
  • Protein arrays
  • RON
  • Signal transduction
  • BRUTONS TYROSINE KINASE
  • HOMEOBOX GENE CDX2
  • B-CELL EXPANSION
  • PRE-B
  • TUMOR-SUPPRESSOR
  • HEMATOLOGICAL MALIGNANCIES
  • PROTEIN SLP-65
  • EXPRESSION
  • CANCER
  • P73

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