Lineage-Specific TOP2A Cleavage Landscape in Leukemia Cell

Topoisomerases II (TOP2) play role in relief of torsional stress during DNA replication and gene transcription, and TOP2 is also a target of anticancer agents which cause secondary leukemia. To address cell lineage-specific TOP2A cleavage relative to leukemia, here we profile genome-wide TOP2A cleavage in human acute lymphoblastic leukemia (ALL) cell line CEM, and compare to TOP2A cleavage landscape of chronic myelogenous leukemia (CML) cell line K562. We find that TOP2A cleavage activity are correlated with chromosome length, suggesting that TOP2A cleavage is critical for segregation or supercoil relaxation of long chromosomes. Meanwhile, we find that evolutionally conserved TOP2A cleavage cluster regions (CCRs) are depleted in gene promoter and enriched in introns and 3’ UTR, and TOP2A cleavage genes tend to be highly expressed, indicating the conserved function of TOP2A cleavage in promoting transcription elongation and activation. In addition, we found that the oncogenic transcription factor complex TAL1, GATA3 and RUNX1 can further promote the activation of TOP2A cleavage genes by binding to their promoters. Further analysis reveal that native TOP2A cleavage are lineage-specific, which play role in cell commitment and leukemia development , while drug-enhanced TOP2A cleavage promote apoptosis of cancer cells in both ALL and CML.Taken together, our findings suggest that native TOP2A cleavage function in long chromosome segregation and transcription activation, and together with the transcriptional regulatory factors shape the commitment of leukemia cell. Global TOP2A-cleavage cluster region in human CEM cell tread with different TOP2 poisons.