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Editorial
. 2017 Oct 11;8(55):93301-93302.
doi: 10.18632/oncotarget.21752. eCollection 2017 Nov 7.

Targeting cistrome and dysregulated transcriptome of post-MPN sAML

Srdan Verstovsek  1 , Warren Fiskus  1 , Taghi Manshouri  1 , Kapil N Bhalla  1
Affiliations
Editorial

Targeting cistrome and dysregulated transcriptome of post-MPN sAML

Srdan Verstovsek et al. Oncotarget. .
No abstract available

Keywords: BETP-PROTAC; BETi; JAKi-persister/resistant; ruxolitinib; sAML.

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Figures

Figure 1
Figure 1. Genetic and epigenetic alterations in sAML create a dysregulated transcriptome susceptible to BET inhibitor therapy
Mutations in JAK2, MPL, CALR, CBL, as well as less common genetic alterations in SOCS2 and LNK phosphorylate and increase activity of JAK2/STAT5/3. Along with MYC and other transcription factors, STAT5/3 recruits HATs and BETP to super-enhancers of growth and survival promoting oncogenes, e.g., MYC, BCL-xL, PIM1 and CDK4/6 and induces their transcript elongation through RNAP2. The epimutations in TET2, IDH2, DNMT3A, EZH2 and SRSF2 also impact the cytosine and histone methylation at enhancers and promoters, contributing to the dysregulated transcriptome. Activated JAK2 in the nucleus phosphorylates PRMT5, thereby disrupting its binding to MEP50, inhibiting symmetric arginine methyltransferase activity and de-repressing transcription. Nuclear JAK2 also tyrosine-phosphorylates H3K41, disrupting the binding of HP1α to chromatin, again de-repressing transcription. Collectively, the resulting dysregulated transcriptome is responsible for the aggressive phenotype and treatment-refractoriness of post-MPN sAML.
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