Genetic Details of Leukemia Resistance

Two gene alterations pair up to promote the growth of leukemia cells and their escape from anticancer drugs, according to new research.

Chronic myeloid leukemia (CML) is an aggressive cancer of the blood that is often treated with imatinib (Gleevec). Although imatinib is highly effective, some cancer cells can develop resistance to the drug. The mechanism that drives this resistance is not completely understood, but evidence suggests that cancerous stem-like cells are particularly resistant and help to perpetuate disease. These cells are known as leukemia-initiating cells.

CML stem-like cells rely on the protein β-catenin for their survival and maintenance. When this protein is deleted in mice, cancer growth is delayed. Another protein, IRF8, inhibits the survival of cells and is often reduced in CML cells, particularly in patients with advanced disease.

In the normal development of blood cells, when β-catenin is activated, IRF8 is upregulated, and then the oncogenic functions of β-catenin are limited. When IRF8 is deficient, the growth of CML becomes dependent on β-catenin.

A group of scientists from the Max Delbrück Center for Molecular Medicine in Berlin, Germany, have demonstrated that CML cells with activating β-catenin mutations are particularly resistant to imatinib. Resistance is boosted further when this defect teams up with those that abolish IRF8 expression, rendering CML cells highly aggressive in mice. In fact, in CML cells lacking IRF8, β-catenin activation was essential for the cell's growth and survival.

The researchers identified β-catenin as a protein that amplifies genes that regulate the progression of CML to the blast crisis stage. When β-catenin is activated, a preexisting LRF8-deficient gene signature is enhanced.

Combined treatment with drugs that restore the expression of IRF8 and those that inactivate β-catenin may force these cells to surrender to treatment, preventing fatal leukemia progression. This study was published in The Journal of Experimental Medicine (2013; doi:10.1084/jem.20130706).

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