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Targeting Leukemia Cell's Gene ‘Addiction’ Offers New Treatment

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An international team of scientists studying acute forms of leukemia has identified a new drug target to inhibit the genes critical for diseased cell growth.

The research, reported in EMBO Molecular Medicine, reveals how leukemia cells become "addicted" to genes, and if targeted could prevent diseased cells from developing.

The University of Vienna team, led by Dr Veronika Sexl, carried out their research on acute lymphoid leukemia (ALL) and chronic myelogenous leukemia (CML), which can be caused by a fusion protein, bcr-abl, created through the joining of two or more genes originally coded for separate proteins.

An oncogene is a gene that, when mutated or expressed at high levels, helps turn a normal cell into a tumor cell. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of CML. The fusion protein has also been associated with ALL. Each is a form of cancer of the white blood cells.

This fusion of genes results in a complex "tumor-supporting network" that allows leukemic cells to survive and proliferate long after the body has signaled for their programmed death. Inhibitor drugs can block these survival signals and lead to leukemia cell death, but there are several mutations that can resist these inhibitors, making them ineffective in some patients.

The team investigated an alternative treatment strategy after finding that sequence-specific DNA binding factors—Stat3 and Stat5—connect to proteins and act as a fuel that enables leukemia cell growth. They found Stat3 and Stat5 are required in the development of bcr-abl, but once established only Stat5 is necessary to keep leukemic cells alive. In mutated forms of bcr-abl, leukemia cells that are resistant to inhibiting drugs such as Imatinib, are still dependent on Stat5 for survial.

"Cancer cells undergo extensive adaptations in their signaling and metabolic pathways, thereby becoming dependent on certain genes," said Sexl. "In fact the activity of these genes can become self-limiting for a cancer cell."

The team coined the term 'Non-oncogene addiction' (NOA) to describe this newly discovered phenomenon of gene dependency. When these critical genes are inhibited within the signaling network it is predicted to cause system failure and halt the growth of leukemia cells.

"We have demonstrated that bcr-abl leukemia cells are addicted to Stat5 to maintain their leukemic state, said Sexl. "Stat5 has an Achilles' heel in the signaling network downstream of bcr-abl, so by inhibiting Stat5 we may have a novel therapeutic approach for treating leukemia."

Lynette Summerill, is an award-winning journalist who lives in Scottsdale, Arizona. In addition to writing about cancer-related issues, she writes a blog, Nonsmoking Nation, which follows global tobacco news

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