Targeting the Mechanism of Differentiation Arrest in a Novel Model of Acute Leukemia
Infant acute leukemias (arising in children less than one year old) makes up a unique subset of leukemias that are particularly lethal and that are characterized by recurrent mutations in one gene. This gene has been termed the mixed lineage leukemia (or MLL) gene, and mutations in MLL are found in the majority of infant leukemias as well as in smaller proportions of childhood and adult leukemias. The mutations in MLL are intriguing, because they are the result of chromosomal breakage which abnormally joins the MLL gene to a variety of partner genes. These mutant "fusion" genes disrupt normal blood development, and lead to immature cells which no longer respect normal bone marrow regulation. This lack of respect for normal development eventually results in leukemia as these immature cells accumulate in the bone marrow and the blood.
Despite the multiple partners of MLL, they all seem to act by increasing the level of another gene termed HoxA9. HoxA9 is a critical gene during development, but needs to be turned off as cells mature. MLL-partners prevent HoxA9 from being switched off. HoxA9 thus appears to be a common pathway in the development of leukemia, and an attractive target for drug development. We have developed a new leukemia cell line with a built-in reporter such that the cells turn fluorescently green when the HoxA9 pathway is inhibited. These cells will allow us to understand how HoxA9 is working, and will allow us to identify drugs which turn off the HoxA9 pathway. Hopefully these anti-HoxA9 and anti-MLL-based drugs will be useful in the treatment of infant leukemia.
