Two is not always better than one, especially in the case of what causes one type of leukemia.
Dimeric Notch signaling complex on DNA. The purple represents two Notch molecules interacting together with the other members of the transcriptional acitvation complex (CSL-orange, Mastermind-yellow) on DNA. Credit: Lili Guo, University of Pennsylvania School of Medicine
The lab of Warren Pear, MD, PhD, professor of Pathology and Laboratory Medicine at the University of Pennsylvania School of Medicine, is the first to show that the coming together of two proteins in a process called dimerization is a key step in causing cancerous cell replication in certain tumors in mice.
Previous work from the Pear lab and others has shown that molecular signals associated with the protein, called Notch, is required for the proper development of white blood cells, in particular T cells. Notch signals must be precisely controlled as mutations in Notch that cause increased signaling occur in the vast majority of T-cell acute lymphoblastic leukemias, which make up about 15 to 20 percent of childhood leukemias. Growth of these leukemias can be stopped in mice using new kinds of Notch pathway inhibitors. T-cell leukemia is driven by strong Notch signals and do not arise if Notch can’t dimerize. However, inhibiting Notch dimerization allows other Notch-dependent functions to occur, such as T-cell development. This suggests that dimerization inhibitors may block a subset of Notch functions, such as leukemia induction, without causing the toxicity of the current generation of wider-acting Notch inhibitors. The Pear team describe their findings in Genes & Development.
