Survey of activated FLT3 signaling in leukemia.

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...

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Autores principales:	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 J Druker, Michael C Heinrich, John Rush, Roberto D Polakiewicz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1023d0cf89bb45dc84d23254aa8bce3c
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spelling	oai:doaj.org-article:1023d0cf89bb45dc84d23254aa8bce3c2021-11-18T06:55:00ZSurvey of activated FLT3 signaling in leukemia.1932-620310.1371/journal.pone.0019169https://doaj.org/article/1023d0cf89bb45dc84d23254aa8bce3c2011-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21552520/?tool=EBIhttps://doaj.org/toc/1932-6203Activating 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.Ting-lei GuJulie NardoneYi WangMarc LoriauxJudit VillénSean BeausoleilMeghan TuckerJon KornhauserJianmin RenJoan MacNeillSteven P GygiBrian J DrukerMichael C HeinrichJohn RushRoberto D PolakiewiczPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 4, p e19169 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 J Druker Michael C Heinrich John Rush Roberto D Polakiewicz Survey of activated FLT3 signaling in leukemia.
description	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.
format	article
author	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 J Druker Michael C Heinrich John Rush Roberto D Polakiewicz
author_facet	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 J Druker Michael C Heinrich John Rush Roberto D Polakiewicz
author_sort	Ting-lei Gu
title	Survey of activated FLT3 signaling in leukemia.
title_short	Survey of activated FLT3 signaling in leukemia.
title_full	Survey of activated FLT3 signaling in leukemia.
title_fullStr	Survey of activated FLT3 signaling in leukemia.
title_full_unstemmed	Survey of activated FLT3 signaling in leukemia.
title_sort	survey of activated flt3 signaling in leukemia.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/1023d0cf89bb45dc84d23254aa8bce3c
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_version_	1718424212277821440

Survey of activated FLT3 signaling in leukemia.

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