Molecular targeting of MLL-rearranged leukemia cell lines with the synthetic peptide PFWT synergistically enhances the cytotoxic effect of established chemotherapeutic agents.
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.
Bennett
Cecily A
CA
Department of Epidemiology, Tulane University, New Orleans, LA 70112, United States.
Winters
Amanda C
AC
Barretto
Nisha N
NN
Hemenway
Charles S
CS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009336:Necrosis; D009687:Nuclear Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000494:pharmacology*; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D009687:Nuclear Proteins; D010446:Peptide Fragments; D035602:Transcriptional Elongation Factors; D003561:Cytarabine; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D005047:Etoposide; D011495:Histone-Lysine N-Methyltransferase