ABSTRACT
Misregulation of transcription elongation is proposed to underlie the pathobiology of MLL leukemia. AF4, AF9, and ENL, common MLL fusion partners, are found in complex with positive transcription elongation factor b (P-TEFb). AF9 and its homolog ENL directly interact with AF4 within these complexes. Previously, we designed a peptide that mimics the AF9 binding domain of AF4 and reported that MLL leukemia cell lines are inhibited by it. Extending these studies, we have modified the peptide design in order to avoid recognition by proteases. The peptide is as effective as its predecessor in vitro and enhances survival in mice bearing MLL leukemia cell lines.
Subject(s)
Leukemia/drug therapy , Myeloid-Lymphoid Leukemia Protein/metabolism , Peptides/pharmacology , Transcriptional Elongation Factors/metabolism , Animals , Binding Sites , Cell Line , DNA-Binding Proteins/metabolism , Female , HEK293 Cells , Humans , Leukemia/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Targeted Therapy , Nuclear Proteins/metabolism , Peptide Hydrolases/metabolism , Protein Binding/drug effectsABSTRACT
MLL leukemias are characterized cytogenetically by reciprocal translocations of the MLL gene at 11q23 and clinically by unfavorable outcomes. Evidence indicating that MLL leukemias are resistant to apoptosis encourages the identification of agents that induce cell death by other mechanisms. The AF4-mimetic peptide PFWT induces necrosis in the t(4;11) leukemia cell line, MV4-11. Treatment of MV4-11 cells with PFWT in combination with four chemotherapeutic compounds results in sequence-dependent synergy, induction of both apoptotic and necrotic cell death, and inhibition of MV4-11 clonogenicity. Therefore, PFWT holds promise as a therapy for MLL leukemias that augments the effects of several clinically available chemotherapeutic agents.
