AMKL chimeric transcription factors are potent inducers of leukemia
- 8 February 2017
- journal article
- research article
- Published by Springer Science and Business Media LLC in Leukemia
- Vol. 31 (10), 2228-2234
- https://doi.org/10.1038/leu.2017.51
Abstract
Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.Keywords
This publication has 45 references indexed in Scilit:
- Mapping of MN1 Sequences Necessary for Myeloid TransformationPLOS ONE, 2013
- The genetic basis of early T-cell precursor acute lymphoblastic leukaemiaNature, 2012
- RAS oncogenes: weaving a tumorigenic webNature Reviews Cancer, 2011
- Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interactionEuropean Journal of Human Genetics, 2011
- Genome-wide Analysis of Simultaneous GATA1/2, RUNX1, FLI1, and SCL Binding in Megakaryocytes Identifies Hematopoietic RegulatorsDevelopmental Cell, 2011
- Mediator and cohesin connect gene expression and chromatin architectureNature, 2010
- GATA-2 Reinforces Megakaryocyte Development in the Absence of GATA-1Molecular and Cellular Biology, 2009
- EWS/FLI-1 Induces Rapid Onset of Myeloid/Erythroid Leukemia in MiceMolecular and Cellular Biology, 2007
- Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9Nature, 2006
- Persistent Transactivation by Meis1 Replaces Hox Function in Myeloid Leukemogenesis Models: Evidence for Co-Occupancy of Meis1-Pbx and Hox-Pbx Complexes on Promoters of Leukemia-Associated GenesMolecular and Cellular Biology, 2006