St. Jude finds factors that accelerate resistance to targeted therapy in lymphoblasti...(mber 15 issue of Genes & Development. ....)

The findings of the study not only suggest why Ph+ ALL is often insensitive to imatinib, but also imply that doctors might identify patients at high risk of failing this treatment by determining whether their leukemic cells lack the Arf gene, said Richard T. Williams, M.D., Ph.D., an assistant member in the St. Jude Department of Oncology and the papers first author. The development of drugs that also block the ability of other factors in the bone marrow to sustain the leukemic cells should render them more susceptible to imatinib and improve the outcome of ALL patients who are resistant to current forms of therapy. Discovery of the Philadelphia chromosome in the 1960s represented the first identification of a chromosome abnormality found in a specific kind of cancer. Ph+ ALL occurs in about 30 percent of all adult, but in only 4 percent of childhood cases. Its presence signals that patients of any age will likely have poor outcomes.

This study strongly suggests that a widely held explanation for how leukemias arise is not universally applicable. This view holds that leukemias arise from rare cancer stem cells, which do not make up the bulk of the tumor, but are the only cells required to regenerate the cancer after treatment, Williams said. However the new St. Jude study reveals that the combination of BCR-ABL activity and inactivation of Arf are sufficient to generate a uniform population of leukemia-initiating cellsany one of which can expand and induce rapidly fatal disease. Rather than comprising only a rare minority of cancer stem cells, each of these ALL cells is able to trigger and propagate the disease, so an effective therapy has to prevent the multiplication of each and every one of them.