An international team of scientists studying acute forms of leukemia have identified a new drug target to inhibit the genes which are vital for the growth of diseased cells. The research, reported in EMBO Molecular Medicine, reveals how leukemia cells become 'addicted' to genes, which if targeted could prevent diseased cells from developing.
The team, led by Dr Veronika Sexl from the University of Vienna, carried out their research on acute lymphoid leukemia (ALL) and chronic myelogenous leukemia (CML), which can both be caused by fusion protein, Bcr-Abl, created through the joining of two or more genes originally coded for separate proteins.
This joining of genes results in a complex tumor supporting 'network' which supports the growth and survival of the leukaemic cells. Inhibitor drugs such as 'Imatinib' can block vital signals and lead to leukemia cell death, but there are several mutations which can resist these inhibitors, making them ineffective.
As an alternative strategy the team investigated transcription factors Stat3 and Stat5 which are linked to bcr/abl-induced transformation. The team tested whether Stat3 and Stat5, acting downstream of Bcr-Abl are critical for leukemia maintenance and if they could be a alternative target for treatment.
"We developed a tumour-specific gene-deletion approach to analyse the roles of Stat5 and Stat3 in Bcr/Abl-induced leukemia growth," said Sexl. "We discovered that both factors are required for the development of Bcr-Abl, but once established only Stat5 is crucial for the survival and growth of leukemic Cells."
Even mutated forms of bcr-abl, leukemia cells, which are resistant to inhibiting drugs such as Imatinib, are still dependent on Stat5.
"Cancer cells undergo extensive adaptations in their signalling and metabolic pathways, thereby becoming dependent on certain genes," said Sexl. "In fact the activity of these genes can become limiting for a cancer cell."
The term 'Non-oncogene addication' (NOA) has been coined to describe this phenomenon of gene dependency and inhibiting these critical genes within the signalling network is predicted to cause system failure and halt the growth of leukemia cells.
"In this study we demonstrated that bcr-abl, leukemia cells are addicted to Stat5 to maintain the leukameic state, concluded Sexl. "We've identified Stat5 as an Achilles' heel in the signalling network downstream of Bcr-Abl. Thus, inhibition of Stat5 may provide a novel therapeutic approach for treatment of leukemia."
- Andrea Hoelbl, Christian Schuster, Boris Kovacic, Bingmei Zhu, Mark Wickre, Maria A. Hoelzl, Sabine Fajmann, Florian Grebien, Wolfgang Warsch, Gabriele Stengl, Lothar Hennighausen, Valeria Poli, Hartmut Beug, Richard Moriggl, Veronika Sexl. Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia. EMBO Molecular Medicine, 2010; 2 (3): 98 DOI: 10.1002/emmm.201000062
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