FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs
| Autor: | Marcos J. Araúzo-Bravo, Verónica Ayllón, Oscar Navarro-Montero, Pedro J. Real, Verónica Ramos-Mejía, Clara Bueno, Pablo Menendez, Damia Romero-Moya, Rosa Montes |
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| Rok vydání: | 2013 |
| Předmět: |
Oncogene Proteins
Fusion Immunology CD34 Mice SCID Biology Biochemistry Mice Downregulation and upregulation hemic and lymphatic diseases medicine Animals Humans Cell Lineage Progenitor cell neoplasms Cells Cultured Embryonic Stem Cells Gene Expression Profiling Cell Differentiation hemic and immune systems Cell Biology Hematology Cell cycle Hematopoietic Stem Cells Microarray Analysis medicine.disease Fusion protein Embryonic stem cell Hematopoiesis Cell biology Enzyme Activation Haematopoiesis Leukemia fms-Like Tyrosine Kinase 3 embryonic structures Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Blood. 121:3867-3878 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Mixed-lineage leukemia (MLL)-AF4 fusion arises prenatally in high-risk infant acute pro-B-lymphoblastic leukemia (pro-B-ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hematoendothelial specification but was insufficient for transformation, suggesting that additional oncogenic insults seem required for MLL-AF4-mediated transformation. MLL-AF4+ pro-B-ALL expresses enormous levels of FLT3, occasionally because of activating mutations, thus representing a candidate cooperating event in MLL-AF4+ pro-B-ALL. Here, we explored the developmental impact of FLT3 activation alone, or together with MLL-AF4, in the hematopoietic fate of hESCs. FLT3 activation does not affect specification of hemogenic precursors but significantly enhances the formation of CD45(+) blood cells, and CD45(+)CD34(+) blood progenitors with clonogenic potential. However, overexpression of FLT3 mutations or wild-type FLT3 (FLT3-WT) completely abrogates 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 affects hESC specification rather than proliferation or survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling of hESC-derived CD45(+) cells supports the FLT3-mediated inhibition of hematopoiesis in MLL-AF4-expressing hESCs, which is associated with large transcriptional changes and downregulation of genes involved in hematopoietic system development and function. Importantly, FLT3 activation does not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells, suggesting the need of alternative (epi)-genetic cooperating hits. |
| Databáze: | OpenAIRE |
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