Background
MLL-rearranged (MLLr) leukemia is an aggressive subtype of acute leukemia with particularly poor prognosis. A chromosomal translocation affecting the MLL (KMT2A) gene on chromosome 11 gives rise to a fusion protein with the MLL N-terminal and the C-terminal of over 100 different fusion partners, in which AF4 is the most common. MLLr fusion proteins cause proliferation and a block in the hematopoietic differentiation ultimately leading to leukemia.
In the Kn?velsrud lab, we have found that expressing the human MLL-AF4 oncogene in the hematopoietic system of the fruit fly (Drosophila melanogaster) induces a leukemia-like phenotype. We have also shown that this phenotype is dependent on the fruit fly equivalents of known interactors responsible for the leukemogenesis in human disease and we have proven its relevance as a drug discovery platform.
Interestingly, our lab has also discovered that the leukemic oncogene MLL-AF4 promotes a tumor defense-like mechanism when expressed in a non-hematopoietic tissue, the fat body in Drosophila larvae. Here, the expression of the oncogene leads to disintegration of the tissue and cell death through autophagy and caspase activity, a sharp contrast to the over-proliferation of MLL-AF4-expressing fly hemocytes.
In this master’s project, we aim to improve our mechanistic understanding of the autophagy and cell death induced by the leukemic oncogene in fat body cells. Our findings indicate that the histone methyltransferase trr, homolog of mammalian MLL3/MLL4, rescues the reduction of cell size promoted by the oncogene by potentially blocking the autophagic flux.
Aim of Project
The aim of this project is to get a better understanding of how trr may regulate autophagy in the fly fat body. This as a step towards unraveling the genetic framework supporting MLL-rearranged leukemia with the long-term goal of unearthing novel targets for therapy for patients suffering from the disease.
Methodology
The student will be working with the model organism Drosophila melanogaster. They will use common Drosophila genetic tools such as UAS-GAL4 and FLP-FRT to express or knock down genes of interest. The responses of the genetic manipulations will then be examined through common wet lab methods such as immunofluorescence imaging, RT-qPCR and western blot.
About the The Cell Stress and Cancer group
The Cell Stress and Cancer group led by Helene Kn?velsrud is located at Domus Medica as a part of the Section of biochemistry, Department of Molecular Medicine at the Institute of Basic Medical Sciences.
The Cell stress and Cancer group is focused on two main goals:
- to understand how autophagy is switched off in vivo
- to unravel mechanisms of autophagy involvement in cancer biology.
We make use of model organisms as well as primary material from cancer patients to study several basic problems in autophagy and cancer.
If you're interested in this project, please contact main supervisor Aina Louise C. Haukeland at alhaukel@uio.no
Relevant literature
- Johannessen, J. A., Formica, M., Haukeland, A. L. C., Br?then, N. R., Al Outa, A., Aarsund, M., Therrien, M., Enserink, J. M., & Kn?velsrud, H. (2023). The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae. iScience, 26(10), 107726. https://doi.org/10.1016/j.isci.2023.107726
- Meyer, C., Larghero, P., Almeida Lopes, B., Burmeister, T., Gr?ger, D., Sutton, R., Venn, N. C., Cazzaniga, G., Corral Abascal, L., Tsaur, G., Fechina, L., Emerenciano, M., Pombo-de-Oliveira, M. S., Lund-Aho, T., Lundán, T., Montonen, M., Juvonen, V., Zuna, J., Trka, J., … Marschalek, R. (2023). The KMT2A recombinome of acute leukemias in 2023. Leukemia, 37(5), 988–1005. https://doi.org/10.1038/s41375-023-01877-1
- Slany, R. K. (2009). The molecular biology of mixed lineage leukemia. Haematologica, 94(7), 984–993. https://doi.org/10.3324/haematol.2008.002436
- Winters, A. C., & Bernt, K. M. (2017). MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches. Front Pediatr, 5, 4. https://doi.org/10.3389/fped.2017.00004