Fusion proteins cause AML by inducing phenotype maintenance, repressing DNA repair

Acute myeloid leukemia (AML)-associated fusion proteins cause the disease by inducing genes involved in the maintenance of the stem cell phenotype and repressing DNA repair genes. This preliminary understanding, at the molecular and biological level, may lead to more targeted treatments, suggest Italian scientists.

A team led by Dr. Myriam Alcalay from the European Institute of Experimental Oncology in Milan used DNA microarray technology to assess gene expression changes induced by three AML fusion proteins. They found 1,555 genes regulated by a least two of these fusion proteins, according to a paper in the December issue of The Journal of Clinical Investigation.Functional studies confirmed that AML fusion protein expression activates the Jagged1/Notch pathway, leading to increased stem cell renewal, and provokes accumulation of DNA damage.”The identification of specific proteins whose activity is altered in AMLs is of obvious importance to the possibility of identifying drug targets,” Dr. Alcalay told Reuters Health.Next the team will try to “characterize gene expression profiles of subpopulations of leukemic stem cells, with the aim of defining the molecular signature of the ‘target cell’ of leukemic events,” Dr. Alcalay said.They also plan to “analyze the difference at a molecular level of the ‘pre-leukemic’ phase – the latency period that elapses between fusion protein expression and frank leukemia – and the leukemic phase, with the aim of identifying secondary genetic hits,” he added.(Source: J Clin Invest 2003;112:1751-1761: Reuters Health: Megan Rauscher: December 25, 2003: Oncolink)