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Novel therapeutic approach for leukaemia

(Vienna, 3 March 2010) Scientists from the laboratory headed by Veronika Sexl at the Institute of Pharmacology of MedUni Vienna have uncovered a key to the successful treatment of leukaemia. The study about the transcription factor Stat5 was published in “EMBO Molecular Medicine”.

For their growth all body cells require signals that trigger the cells’ reproduction and renewal. The signals are received via the so-called growth factors. These messenger substance dock onto receptors on the cell surface. In this way the receptor is activated and sends signals to the cell’s interior where so-called transcription factors (i.e. proteins that can bind to the genetic material) transmit the signal to the DNA where the cell division is then triggered.

Also cancer cells need this signal transmission for their growth, it is therefore decisive for the development as well as the maintenance of every form of cancer. For leukaemia in which the fusion gene Bcr/Abl occurs (these are some 95 percent of chronic myelotic leukaemia and some 20 percent of acute lymphatic leukaemia in adults) Mag.a Andrea Hölbl and Dr. Christian Schuster from the laboratory of Univ. Veronika Sexl at the Institute of Pharmacology of MedUni Vienna were able to identify the transcription factor Stat5 as one decisive factor and possible therapeutic approach.

Cancer stem cells are dependent on Stat5
In a leukaemia model on mice  in which the disease can be emulated in every detail, the scientists demonstrated that Stat5 and its close relative Stat3 are necessary for the development of this Bcr/Abl-induced leukaemia. Following the establishment of leukaemia, the signal patterns of the leukaemia cells changes and Stat3 loses its importance. But without the signals transmitted via Stat5 the cells cannot survive. The cancer stem cells are also dependent on the transcription factor Stat5. This discovery has also attained major importance due to the fact that the blockage of Stat5 is tolerated surprisingly well in the entire organism of the mouse model and also that mutations of Bcr/Abl remained dependent on Stat5. In these findings, Veronika Sexl sees the starting point for developing therapeutic strategies which are based on the transcription factor Stat5: “Currently established therapies can only insufficiently eliminate leukaemic stem cells.”

Success due to international cooperation
The work was conducted at the laboratory of Veronika Sexl at the Institute of Pharmacology of the Medical University of Vienna, with the involvement of the Ludwig-Boltzmann Institute of Cancer Research (LBI-CR), the Center for Molecular Medicine of ÖAW (CeMM), the Institute of Molecular Pathology (IMP), a working group of the National Institute of Health (NIH) and Turin University (UNITO). The two leading authors Andrea Hölbl and Christian Schuster started to conduct their study within the framework of their PhD studies at MedUni Vienna, Andrea Hölbl currently works as a PostDoc at the Institute of Pharmacology. The project has been made possible through the financial support of the Austrian Science Fund FWF (SFB 28), the Vienna Science, Technology and Research Fund (WWTF) and the GenAu programme DRAGON.

» Original work
Hoelbl.A, Schuster.C, Kovacic.B, Zhu.B, Wickre.M, Hoelzl.M, Fajmann.S, Grebien.F, Warsch.W, Stengl.G, Henninghausen.L, Poli.V, Beug.H, Moriggl.R, Sexl.V, “Stat5 is indespensible for the maintenance of bcr/abl-positive leukaemia,” EMBO, Wiley-Blackwell, March 2010. DOI: 10.1002/emmn.201000062

» Picture: Blood smear of a CML patient with
Bcr/Abl positive tumour cells (dark/violet), erythrocytes (light)
© Klaus Lechner