MLL Translocations: Fusion Proteins and Stem Cell Program

Coordinator:		Prof. Dr. Rolf Marschalek
Institution:		Institut für Pharmazeutische Biologie, Goethe-Universität Frankfurt/Main, Biozentrum
Homepage:		www.pharmazie.uni-frankfurt.de/PharmBiol/Marschalek

Chromosomal translocations of the human MLL gene are correlated with acute leukemias in pediatric and adult AML or ALL. The most frequent genetic rearrangement of MLL is the chromosomal translocation t(4;11)(q21;q23) that can be recurrently diagnosed in about 40% of all MLL-rearranged ALL patients (Meyer, 2009). Since treatment of t(4;11)-leukemias results in very poor outcome, it is necessary to study the disease mechanism in more detail. For this purpose, we have developed in recent years in vitro (Gaussmann et al., 2007) and in vivo model systems (Bursen, submitted) to study certain aspects of t(4;11) leukemia. In these model systems, we have already demonstrated that the AF4-MLL fusion protein has an important impact on disease development, either alone or in conjunction with the MLL-AF4 fusion protein.
In aim 1 of our study we want to investigate gene expression profiles (GEPs) of t(4;11) patients by using a modified approach. Single GEPs of pediatric t(4;11) patients will be normalized against GEPs of three independent normal bone marrow aspirates. Only consistently deregulated genes will then be used for further analysis. Identified signatures will then be used to investigate interesting candidate genes in more detail.
Aim 2 of this study will focus on a recently discovered stem cell program in t(4;11) cells. Murine fibroblasts stably transfected with MLL-AF4 and AF4-MLL fusion genes displayed a 16-fold transcriptional upregulation of the Nanog gene in gene expression profiles. This initial finding was then confirmed in t(4;11) patients (Gaussmann, 2007). Interestingly, transcripts of the “core Nanog network“ were found to be expressed in t(4;11) cells in a similar fashion as in embryonic stem cells. Therefore, we want to investigate this genetic program in more detail, asking the question on how this genetic program can be artificially turned on on leukemia cells and what kind of effects are mediated by this genetic program to influence the physiology of the disease.

Gaussmann et al (2007). 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. Oncogene 26, 3352-3363.
Meyer et al (2009). New Iinsights into the MLL recombinome of acute leukemias. Leukemia 2009 Mar 5 [Epub ahead of print].
Bursen et al (2009). AF4-MLL is capable of inducing ALL in mice without requirement of MLL-AF4. Submitted.


Additional relevant Internet links:
Diagnostic Center of Acute Leukemia DCAL
Forschergruppe "Pathologische Genprodukte und ihre Wirkmechanismen"