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Established cancer therapeutics are effective against aggressive blood cancer with mutations in STAT5

Research teams from Vienna investigated a typical mutation in STAT5 that renders tumors more aggressive but susceptible to established drugs.

The prestigious Journal of Clinical Investigation is now publishing an important contribution to leukemia and lymphoma research. This study by scientists at the Veterinary University of Vienna, the Medical University of Vienna, the Research Center for Molecular Medicine of the Academy of Sciences, and the Ludwig Boltzmann Institute for Cancer Research focused on the mutated form of the STAT5B oncogene.

Figure: Schematic of STAT5B mutations identified in leukemia and lymphoma patients. Each dot represents 1 patient

 

Usually, STAT5 controls maturation and proliferation in blood cells, but too much STAT5 can contribute to cancer. STAT5 activation is due to cytokines that bind to a receptor on the cell surface, resulting in a short-term activation of STAT5 inside the cell. The researchers identified a mutation in the STAT5B cancer gene that is present in treated blood cancer patients and extends STAT5B activity. This mutation triggers therapy resistance and the cancer cells become dependent on this active STAT5, comparable to drug addiction. If you removed STAT5 activation, the tumor cells would die. Lead investigator Prof. Moriggl states, "This mutation makes cancer cells more aggressive, but we've found that the cells continue to need growth signals from cytokines to divide uncontrollably." In a newly established animal model drugs targeting cytokine mediated activation of STAT5 made tumors disappear. This is an important discovery for the treatment of aggressive lymphomas, which often show strong activation of STAT5.

Please check also the commentary by Lisa N. Heppler and David A. Frank

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STAT5BN642H is a driver mutation for T-cell neoplasia,

Ha Thi Thanh Pham, Barbara Maurer, Michaela Prchal-Murphy, Reinhard Grausenburger, Eva Grundschober, Tahereh Javaheri, Harini Nivarthi, Auke Boersma, Thomas Kolbe, Mohamed Elabd, Florian Halbritter, Jan Pencik, Zahra Kazemi, Florian Grebien, Markus Hengstschläger, Lukas Kenner, Stefan Kubicek, Matthias Farlik, Christoph Bock, Peter Valent, Mathias Müller, Thomas Rülicke, Veronika Sexl and Richard Moriggl in J Clin Invest. 2018;128(1)