Homing and invasiveness of MLL/ENL leukemic cells is regulated by MEF2C
| Autor: | Andrea Schüler, Martin Forster, Eric N. Olson, Maike Schwieger, Robert K. Slany, Afra Engelmann, Peter J. M. Valk, Michael Arnold, Ruud Delwel, Jürgen Löhler, Carol Stocking |
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| Přispěvatelé: | Hematology |
| Rok vydání: | 2009 |
| Předmět: |
Male
Oncogene Proteins Fusion Immunology Mice SCID Biology Biochemistry Leukemia Myelomonocytic Acute Colony-Forming Units Assay Mice Myelogenous Cell Movement Mice Inbred NOD Transduction Genetic medicine Animals Humans Neoplasm Invasiveness Bone Marrow Transplantation Cell Proliferation Oligonucleotide Array Sequence Analysis Regulation of gene expression Gene Expression Regulation Leukemic MEF2 Transcription Factors Gene Expression Profiling Cell Biology Hematology medicine.disease Fusion protein Neoplasm Proteins DNA-Binding Proteins Leukemia Virus Murine Mice Inbred C57BL Gene expression profiling Leukemia Cell Transformation Neoplastic Myogenic Regulatory Factors Interferon Regulatory Factors Neoplastic Stem Cells Cancer research Female Stem cell IRF8 Myeloid-Lymphoid Leukemia Protein Transcription Factors Homing (hematopoietic) |
| Zdroj: | Blood, 114(12), 2476-2488. American Society of Hematology |
| ISSN: | 0006-4971 |
| Popis: | Acute myelogenous leukemia is driven by leukemic stem cells (LSCs) generated by mutations that confer (or maintain) self-renewal potential coupled to an aberrant differentiation program. Using retroviral mutagenesis, we identified genes that generate LSCs in collaboration with genetic disruption of the gene encoding interferon response factor 8 (Irf8), which induces a myeloproliferation in vivo. Among the targeted genes, we identified Mef2c, encoding a MCM1-agamous-deficiens-serum response factor transcription factor, and confirmed that overexpression induced a myelomonocytic leukemia in cooperation with Irf8 deficiency. Strikingly, several of the genes identified in our screen have been reported to be up-regulated in the mixed-lineage leukemia (MLL) subtype. High MEF2C expression levels were confirmed in acute myelogenous leukemia patient samples with MLL gene disruptions, prompting an investigation of the causal interplay. Using a conditional mouse strain, we demonstrated that Mef2c deficiency does not impair the establishment or maintenance of LSCs generated in vitro by MLL/ENL fusion proteins; however, its loss led to compromised homing and invasiveness of the tumor cells. Mef2c-dependent targets included several genes encoding matrix metalloproteinases and chemokine ligands and receptors, providing a mechanistic link to increased homing and motility. Thus, MEF2C up-regulation may be responsible for the aggressive nature of this leukemia subtype. |
| Databáze: | OpenAIRE |
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