Broad Institute Inhibition of the MLL-AF4-AF9 Interaction in Pediatric Leukemia Inhibitor Probe Project
HTS will be used to discover inhibitors of the binding of AF9 to MLL-AF4, and these inhibitors will be used as tool compounds to probe the mechanistic basis for MLL-R leukemia, and will be tested alone and in combination with existing therapeutic agents against MLL-R leukemia cell lines in culture and murine xenografts. ..more
Andrew Napper,Jefferson Medical College ,email@example.com, 302-298-7209
HTS will be used to discover inhibitors of the binding of AF9 to MLL-AF4, and these inhibitors will be used as tool compounds to probe the mechanistic basis for MLL-R leukemia, and will be tested alone and in combination with existing therapeutic agents against MLL-R leukemia cell lines in culture and murine xenografts.
Aim 1: Run a validated high throughput screen to identify small molecule inhibitor of the interaction of AF4 and AF9.
Aim2: Test cytotoxic and/or anti-proliferative effects of confirmed inhibitors of AF4/AF9 protein/protein interaction in a panel of 6 cell line carrying or not of MLL-AF4 (MLL-R) fusion.
Aim3: Measure direct binding of compounds to AF9.
AF9, MLL AF4, MLL-R leukemia,
Childhood leukemia that develops following rearrangement of the mixed lineage leukemia (MLL) gene to give MLL fusion proteins is aggressive and very difficult to treat. Many of the MLL fusions give rise to leukemia in infants, who are especially vulnerable to the toxic effects of currently used chemotherapy. The prognosis is particularly grim for patients harboring fusion of the MLL protein with the transcription factor AF4 (ALL-1 fused gene from chromosome 4). In infant acute lymphocytic leukemia (ALL), the MLL-AF4 fusion occurs in half of all cases, leading to a five-year event-free survival rate of only 34% . MLL fusions are potent inducers of leukemia, through recruitment of a complex of proteins that activate transcription of the HOX (homeobox) oncogene HOXA9, the expression of which is normally suppressed during white blood cell differentiation. MLL-AF4 binds to the transcription factor AF9, and this MLL-AF4-AF9 interaction has been shown to be a critical component of the transcriptional activation complex that promotes HOX gene expression .