Fig. 4 | Signal Transduction and Targeted Therapy

Fig. 4

From: Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies

Fig. 4

Aberrant recruitment of HAT/HDAC-containing complexes is a general mechanism of leukemogenesis. Chromatin accessibility plays a critical role in regulating cell type-specific gene expression during hematopoiesis but has also been suggested to be abnormally regulated during leukemogenesis. Oncogenic TF or fusion protein binding was found at accessible chromatin regions with aberrant recruitment of the coactivator (CoA) or corepressor (CoR) complexes that affected histone modification patterns, altered the chromatin structure and thereby facilitated DNA accessibility. Furthermore, in some cases, HATs/HDACs are critical to the optimal oncogenic activity of leukemia TFs or fusion proteins via regulating their acetylation levels. Therefore, disrupting the balanced interplay of the epigenetic environment and oncogenic TFs or fusion proteins might be used as a therapeutic strategy. a Upper panel, P300-containing CoA complexes contribute to the self-renewal and leukemogenesis of HSPCs through acetylating the AML1-ETO fusion, which promotes its transcriptional activation and histone H3. b The AML1-ETO fusion recruits CoR complexes consisting of the nuclear receptor corepressor (N-CoR), HDAC1, SIN3 transcription regulator family member A (mSin3A), and DNA methyltransferase 1 (DNMT1), which repress gene transcription by enzymatic deacetylation of histones, DNA methylation, and creation of a repressive chromatin structure. c In APL blast cells, the PML-RARα fusion forms oligodimers and binds DNA through recruitment of the CoR–HDAC complex, which leads to deacetylation of histones and H3K27/H3K9 methylation and subsequently produces a condensed chromatin structure that represses the transcription of target genes. While all-trans retinoic acid (RA) or arsenic trioxide (ATO) mediates degradation of PML-RARα, which is replaced by the RARα/RXR heterodimer, and converts the CoR-HDAC into a CoA–HAT complex that reactivates gene transcription and restores differentiation

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