Title:Epigenetic Mismatches with Mutated Transcribing Genes at Leukemogenic S-Phase Binding/Start Sites – Potential Targets for Therapy with Enzyme Inhibitors
Volume: 7
Issue: 6
Author(s): Gregor Prindull
Affiliation:
Keywords:
Epigenetic enzymes, leukemogenic cell cycle S-phase, transcriptional mismatches, transcription factors, gene, intra S-phase surveillance, cis-regulating chromatin modulators, leukemia, Epigenetic genes
Abstract: This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification
of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is
triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate
from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information
of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e.g. pi)RNA transmitted
between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic
domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication
forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through
leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin
domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription
factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic
genes.
In conclusion: Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with
replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although
mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed
TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive
treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production.
Clinically, classification of leukemias should be based on their epigenetic presentation.
