Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation
Open Access
- 27 November 2006
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 26 (23), 3352-3363
- https://doi.org/10.1038/sj.onc.1210125
Abstract
The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapy-related high-risk acute leukemia. Here, we investigated the biological effects of MLL·AF4, AF4·MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and loss-of-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.Keywords
This publication has 34 references indexed in Scilit:
- Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progressionGenes & Development, 2006
- A murine Mll-AF4 knock-in model results in lymphoid and myeloid deregulation and hematologic malignancyBlood, 2006
- Dissecting self-renewal in stem cells with RNA interferenceNature, 2006
- Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of MllProceedings of the National Academy of Sciences of the United States of America, 2006
- Control of Developmental Regulators by Polycomb in Human Embryonic Stem CellsCell, 2006
- A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technologyOncogene, 2006
- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem CellsCell, 2005
- Interaction of AF4 wild-type and AF4·MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology?Oncogene, 2004
- Modulation of cell cycle by graded expression of MLL-AF4 fusion oncoproteinLeukemia, 2004
- Altered Hox expression and segmental identity in Mll-mutant miceNature, 1995