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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
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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.
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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
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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 |
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Submission date |
Aug 14, 2012 |
Last update date |
Jan 15, 2022 |
Contact name |
Marcos J. Araúzo-Bravo |
E-mail(s) |
mararabra@yahoo.co.uk
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Phone |
+34 943 00 6108
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Organization name |
Max Planck Institute for Molecular Biomedicine
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Department |
Cell and Developmental Biology
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Lab |
Computational Biology and Bionformatics
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Street address |
Rogentstrasse
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City |
Muenster |
ZIP/Postal code |
48149 |
Country |
Germany |
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Platforms (1) |
GPL13607 |
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Feature Number version) |
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Samples (18)
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GSM984946 |
CD45- hemogenic precursors EV rep1 |
GSM984947 |
CD45- hemogenic precursors EV rep2 |
GSM984948 |
CD45- hemogenic precursors FLT3-TKD rep1 |
GSM984949 |
CD45- hemogenic precursors FLT3-TKD rep2 |
GSM984950 |
CD45- hemogenic precursors FLT3-WT rep1 |
GSM984951 |
CD45- hemogenic precursors FLT3-WT rep2 |
GSM984952 |
CD45- hemogenic precursors FLT3-TKD/MLLAF4 rep1 |
GSM984953 |
CD45- hemogenic precursors FLT3-TKD/MLLAF4 rep2 |
GSM984954 |
CD45- hemogenic precursors FLT3-WT/MLLAF4 rep1 |
GSM984955 |
CD45- hemogenic precursors FLT3-WT/MLLAF4 rep2 |
GSM984956 |
CD45+ blood cells EV rep1 |
GSM984957 |
CD45+ blood cells FLT3-TKD rep1 |
GSM984958 |
CD45+ blood cells FLT3-TKD rep2 |
GSM984959 |
CD45+ blood cells FLT3-WT rep1 |
GSM984960 |
CD45+ blood cells FLT3-WT rep2 |
GSM984961 |
CD45+ blood cells FLT3-TKD/MLLAF4 rep1 |
GSM984962 |
CD45+ blood cells FLT3-TKD/MLLAF4 rep2 |
GSM984963 |
CD45+ blood cells FLT3-WT/MLLAF4 rep1 |
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Relations |
BioProject |
PRJNA172840 |
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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