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.
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.
Gaussmann
A
A
Institute of Pharmaceutical Biology/ZAFES, JWG-University Frankfurt, Biocenter, Frankfurt/Main, Germany.
Wenger
T
T
Eberle
I
I
Bursen
A
A
Bracharz
S
S
Herr
I
I
Dingermann
T
T
Marschalek
R
R
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein