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Series GSE40103 Query DataSets for GSE40103
Status Public on Jun 04, 2013
Title FLT3 activation cooperates with MLL-AF4 fusion gene to abrogate the hematopoietic specification of human ESCs
Organism Homo sapiens
Experiment type Expression profiling by array
Summary MLL-AF4 is a hallmark genomic aberration which arises prenatally in high-risk infant acute lymphoblastic leukemia (ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hemato-endothelial specification but was not sufficient for transformation. Additional cooperating genetic insults seem required for MLL-AF4-mediated leukemogenesis. FLT3 is highly expressed in MLL-AF4+ ALL through activating mutations (FLT3-TKD or FLT3-ITD) or increased transcriptional expression, being therefore considered a potential cooperating event in MLL-AF4+ ALL. Here, we explored the developmental impact of FLT3 activation on its own or in cooperation with MLL-AF4 in the hematopoietic fate of hESCs. FLT3 activation did not impact specification of CD45-CD31+ hemogenic precursors but significantly enhanced the formation of CD45+CD34+ and CD45+ blood cells and blood progenitors with clonogenic potential. Importantly, FLT3 activation through FLT3 mutations or FLT3-WT overexpression completely abrogated hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly impacts hESC specification rather than selective proliferation/survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling supported the limited impact of FLT3 activation on hESC specification towards CD45-hemogenic precursors and the enhanced hematopoiesis upon FLT3 activation, and inhibited hematopoiesis upon MLL-AF4 expression in FLT3-activated hESCs which was associated to large transcriptional changes and regulation of master early hematopoietic genes. Also, although FLT3 activation and MLL-AF4 cooperate to inhibit embryonic hematopoiesis the underlying molecular/genetic mechanisms differ depending on how FLT3 activation is achieved. Finally, FLT3 activation did not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells.
Overall design 18 samples were analyzed.
CD45- hemogenic precursors EV, 2 biological rep
CD45- hemogenic precursors FLT3-TKD, 2 biological rep
CD45- hemogenic precursors FLT3-WT, 2 biological rep
CD45- hemogenic precursors FLT3-TKD/MLLAF4, 2 biological rep
CD45- hemogenic precursors FLT3-WT/MLLAF4, 2 biological rep
CD45+ blood cells EV, 1 biological rep
CD45+ blood cells FLT3-TKD, 2 biological rep
CD45+ blood cells FLT3-WT, 2 biological rep
CD45+ blood cells FLT3-TKD/MLLAF4, 2 biological rep
CD45+ blood cells FLT3-WT/MLLAF4, 1 biological rep
Contributor(s) Bueno C, Montes R, Navarro-Montero O, Ayllón V, Ramos-Mejia V, Real PJ, Romero-Moya D, Araúzo-Bravo MJ, Menendez P
Citation(s) 23479570
Submission date Aug 14, 2012
Last update date Jan 15, 2022
Contact name Marcos J. Araúzo-Bravo
Phone +34 943 00 6108
Organization name Max Planck Institute for Molecular Biomedicine
Department Cell and Developmental Biology
Lab Computational Biology and Bionformatics
Street address Rogentstrasse
City Muenster
ZIP/Postal code 48149
Country Germany
Platforms (1)
GPL13607 Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Feature Number version)
Samples (18)
GSM984946 CD45- hemogenic precursors EV rep1
GSM984947 CD45- hemogenic precursors EV rep2
GSM984948 CD45- hemogenic precursors FLT3-TKD rep1
BioProject PRJNA172840

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE40103_RAW.tar 226.0 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

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