A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling

Fms-like tyrosine kinase-3 is a commonly mutated gene in acute myeloid leukemia, with about one-third of patients carrying an internal-tandem duplication of the juxtamembrane domain in the receptor (FLT3-ITD). FLT3-ITD exhibits altered signaling quality, including aberrant activation of STAT5. To id...

Full description

Bibliographic Details
Main Authors:	Caldarelli, A, Müller, J P, Paskowski-Rogacz, M, Herrmann, K, Bauer, R, Koch, S, Heninger, A K, Krastev, D, Ding, L, Kasper, S, Fischer, T, Brodhun, M, Böhmer, F-D, Buchholz, F
Format:	Online
Language:	English
Published:	Nature Publishing Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865536/

id	pubmed-3865536
recordtype	oai_dc
spelling	pubmed-38655362013-12-17 A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling Caldarelli, A Müller, J P Paskowski-Rogacz, M Herrmann, K Bauer, R Koch, S Heninger, A K Krastev, D Ding, L Kasper, S Fischer, T Brodhun, M Böhmer, F-D Buchholz, F Original Article Fms-like tyrosine kinase-3 is a commonly mutated gene in acute myeloid leukemia, with about one-third of patients carrying an internal-tandem duplication of the juxtamembrane domain in the receptor (FLT3-ITD). FLT3-ITD exhibits altered signaling quality, including aberrant activation of STAT5. To identify genes affecting FLT3-ITD-mediated STAT5 signaling, we performed an esiRNA-based RNAi screen utilizing a STAT5-driven reporter assay. Knockdowns that caused reduced FLT3-ITD-mediated STAT5 signaling were enriched for genes encoding proteins involved in protein secretion and intracellular protein transport, indicating that modulation of protein transport processes could potentially be used to reduce constitutive STAT5 signaling in FLT3-ITD-positive cells. The relevance of KDELR1, a component involved in the Golgi-ER retrograde transport, was further analyzed. In FLT3-ITD-expressing leukemic MV4-11 cells, downregulation of KDELR1 resulted in reduced STAT5 activation, proliferation and colony-forming capacity. Stable shRNA-mediated depletion of KDELR1 in FLT3-ITD-expressing 32D cells likewise resulted in reduced STAT5 signaling and cell proliferation. Importantly, these cells also showed a reduced capacity to generate a leukemia-like disease in syngeneic C3H/HeJ mice. Together our data suggest intracellular protein transport as a potential target for FLT3-ITD driven leukemias, with KDELR1 emerging as a positive modulator of oncogenic FLT3-ITD activity. Nature Publishing Group 2013-12 2013-04-12 /pmc/articles/PMC3865536/ /pubmed/23508117 http://dx.doi.org/10.1038/leu.2013.83 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Caldarelli, A Müller, J P Paskowski-Rogacz, M Herrmann, K Bauer, R Koch, S Heninger, A K Krastev, D Ding, L Kasper, S Fischer, T Brodhun, M Böhmer, F-D Buchholz, F
spellingShingle	Caldarelli, A Müller, J P Paskowski-Rogacz, M Herrmann, K Bauer, R Koch, S Heninger, A K Krastev, D Ding, L Kasper, S Fischer, T Brodhun, M Böhmer, F-D Buchholz, F A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
author_facet	Caldarelli, A Müller, J P Paskowski-Rogacz, M Herrmann, K Bauer, R Koch, S Heninger, A K Krastev, D Ding, L Kasper, S Fischer, T Brodhun, M Böhmer, F-D Buchholz, F
author_sort	Caldarelli, A
title	A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
title_short	A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
title_full	A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
title_fullStr	A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
title_full_unstemmed	A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling
title_sort	genome-wide rnai screen identifies proteins modulating aberrant flt3-itd signaling
description	Fms-like tyrosine kinase-3 is a commonly mutated gene in acute myeloid leukemia, with about one-third of patients carrying an internal-tandem duplication of the juxtamembrane domain in the receptor (FLT3-ITD). FLT3-ITD exhibits altered signaling quality, including aberrant activation of STAT5. To identify genes affecting FLT3-ITD-mediated STAT5 signaling, we performed an esiRNA-based RNAi screen utilizing a STAT5-driven reporter assay. Knockdowns that caused reduced FLT3-ITD-mediated STAT5 signaling were enriched for genes encoding proteins involved in protein secretion and intracellular protein transport, indicating that modulation of protein transport processes could potentially be used to reduce constitutive STAT5 signaling in FLT3-ITD-positive cells. The relevance of KDELR1, a component involved in the Golgi-ER retrograde transport, was further analyzed. In FLT3-ITD-expressing leukemic MV4-11 cells, downregulation of KDELR1 resulted in reduced STAT5 activation, proliferation and colony-forming capacity. Stable shRNA-mediated depletion of KDELR1 in FLT3-ITD-expressing 32D cells likewise resulted in reduced STAT5 signaling and cell proliferation. Importantly, these cells also showed a reduced capacity to generate a leukemia-like disease in syngeneic C3H/HeJ mice. Together our data suggest intracellular protein transport as a potential target for FLT3-ITD driven leukemias, with KDELR1 emerging as a positive modulator of oncogenic FLT3-ITD activity.
publisher	Nature Publishing Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865536/
_version_	1612039042215444480

A genome-wide RNAi screen identifies proteins modulating aberrant FLT3-ITD signaling

Similar Items