"MLL-AF9 apparently 'hijacks' Myb to enforce a program of aberrant self-renewal," explains Amy Rappaport, who was a co-first author on the paper, with Johannes Zuber. The team also included Christopher Vakoc, a CSHL Fellow, among others. "The consequences of inhibiting Myb in established leukemia were striking," says Zuber. "Following Myb suppression, mouse leukemia cells invariably lost their aberrant self-renewal ability, resumed their normal cell fate, maturing into white blood cells, and eventually got eliminated." As a consequence, mice harboring this aggressive and chemotherapy-resistant form of AML were cured by inhibiting Myb. The protein's suppression had no adverse impact upon normal white blood cells.
To identify and study genes that are specifically required in cancer cells, the researchers took a systematic approach that demonstrates the power of a series of technological advances made by Lowe's group in concert with several other groups at CSHL. These advances play an important role in CSHL's new Cancer Therapeutic Initiative. The Initiative aims to rapidly identify new therapeutic targets and validate them in mouse models specific for genetic subtypes of human cancer.
In the paper published today, Lowe's team first implemented a rapid strategy to introduce common human AML mutations in mice so that they closely mimicked human AML, both in terms of symptoms and response to treatment. These genetically reprogrammed mice are called "mosaic mice." As a next step, the team used a genetic switch to inactivate the oncogene that gives rise to the "addictive" MLL-AF9 oncoprotein. When MLL-AF9 was suppressed in living mice, the cancers shrank
|Contact: Peter Tarr|
Cold Spring Harbor Laboratory