Survey of activated FLT3 signaling in leukemia

Ting lei Gu, Julie Nardone, Yi Wang, Marc Loriaux, Judit Villén, Sean Beausoleil, Meghan Tucker, Jon Kornhauser, Jianmin Ren, Joan MacNeill, Steven P. Gygi, Brian Druker, Michael Heinrich, John Rush, Roberto D. Polakiewicz

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.

Original languageEnglish (US)
Article numbere19169
JournalPLoS One
Volume6
Issue number4
DOIs
StatePublished - 2011

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leukemia
Protein-Tyrosine Kinases
tyrosine
Leukemia
phosphotransferases (kinases)
myeloid leukemia
Acute Myeloid Leukemia
Phosphorylation
Cells
phosphorylation
Tyrosine
Surveys and Questionnaires
Isotope Labeling
IgE Receptors
Cell Line
cell lines
Mutation
mutation
isotope labeling
Threonine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gu, T. L., Nardone, J., Wang, Y., Loriaux, M., Villén, J., Beausoleil, S., ... Polakiewicz, R. D. (2011). Survey of activated FLT3 signaling in leukemia. PLoS One, 6(4), [e19169]. https://doi.org/10.1371/journal.pone.0019169

Survey of activated FLT3 signaling in leukemia. / Gu, Ting lei; Nardone, Julie; Wang, Yi; Loriaux, Marc; Villén, Judit; Beausoleil, Sean; Tucker, Meghan; Kornhauser, Jon; Ren, Jianmin; MacNeill, Joan; Gygi, Steven P.; Druker, Brian; Heinrich, Michael; Rush, John; Polakiewicz, Roberto D.

In: PLoS One, Vol. 6, No. 4, e19169, 2011.

Research output: Contribution to journalArticle

Gu, TL, Nardone, J, Wang, Y, Loriaux, M, Villén, J, Beausoleil, S, Tucker, M, Kornhauser, J, Ren, J, MacNeill, J, Gygi, SP, Druker, B, Heinrich, M, Rush, J & Polakiewicz, RD 2011, 'Survey of activated FLT3 signaling in leukemia', PLoS One, vol. 6, no. 4, e19169. https://doi.org/10.1371/journal.pone.0019169
Gu TL, Nardone J, Wang Y, Loriaux M, Villén J, Beausoleil S et al. Survey of activated FLT3 signaling in leukemia. PLoS One. 2011;6(4). e19169. https://doi.org/10.1371/journal.pone.0019169
Gu, Ting lei ; Nardone, Julie ; Wang, Yi ; Loriaux, Marc ; Villén, Judit ; Beausoleil, Sean ; Tucker, Meghan ; Kornhauser, Jon ; Ren, Jianmin ; MacNeill, Joan ; Gygi, Steven P. ; Druker, Brian ; Heinrich, Michael ; Rush, John ; Polakiewicz, Roberto D. / Survey of activated FLT3 signaling in leukemia. In: PLoS One. 2011 ; Vol. 6, No. 4.
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