Identification of novel therapeutic targets for leukemia with 11q23 chromosomal translocations
Description
Leukemias with chromosomal translocation at the 11q23 loci are associated with poor prognosis. We are particularly interested in the t(9,11) (q22;q23) translocation that generates the MLL-AF9 fusion gene that triggers AML (Acute Myeloid Leukemia) and the t(4;11) (q21;q23) translocation that generates the MLL-AF4 fusion gene associated with ALL (Acute Lymphoid leukemia). Understanding the functioning of the MLL fusion proteins is crucial for the rationale drug development To begin to address the role of chimeric MLL proteins in leukemogenesis, we have focused on one of the most commonly encountered fusion partners, AF9. The C-terminal ninety amino acids of AF9 are crucial for the leukemic property of MLL-AF9 fusion protein. We wanted to identify the proteins that interact with this domain. We have identified a specific isoform of BCL-6 co-repressor BCoR as an AF9 interacting protein. We also show that this AF9 interacting isoform of BCoR inhibits the transcriptional activity of AF9. We have also identified MLL associated AF4 to be an AF9 interacting protein. Based on this finding we have developed a peptide drug PFWT that inhibits the proliferation of leukemia cells with t(4;11) chromosomal translocation. We show that apoptosis is involved in inhibiting the proliferation of these leukemic cells. In addition to apoptosis, at least one t(4;11) leukemia cell line undergoes morphological changes that suggest differentiation when exposed to the peptide. Importantly, the PFWT peptide does not appear to have any effect on colony forming ability of bone marrow stem cells. Hence, PFWT or derivative compounds may specifically target leukemic cells with t(4;11) translocations and provide an avenue for the development of more effective therapies for babies with acute leukemia Yeast three hybrid experiments show that AF9 can form a stable complex with AF4 and BCoR. Based on this finding, the possibility of BCoR being the transforming factor in acute leukemias with MLL translocations is discussed