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Related Experiment Videos

Core-binding factor leukemia hijacks the T-cell-prone PU.1 antisense promoter.

E van der Kouwe1, G Heller2, A Czibere3

  • 1Department of Medicine I, Division of Hematology and Hemostaseology, and.

Blood
|May 19, 2021
PubMed
Summary

Acute myeloid leukemia (AML) involves reduced PU.1 levels, driven by RUNX factors activating an antisense promoter. This blocks myeloid differentiation, offering a therapeutic target in CBF-AML.

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Area of Science:

  • Hematopoiesis and Cancer Biology
  • Molecular Mechanisms of Gene Regulation
  • Epigenetics and Chromatin Remodeling

Background:

  • The blood system is a critical model for studying cell differentiation and cancer.
  • PU.1 is a master regulator in hematopoietic systems; reduced PU.1 levels are a hallmark of acute myeloid leukemia (AML).
  • Transcriptional dysregulation of PU.1 is implicated in AML pathogenesis.

Purpose of the Study:

  • To elucidate the mechanism of PU.1 transcriptional downregulation in AML.
  • To investigate the role of RUNX transcription factors and antisense transcription in PU.1 regulation.
  • To identify potential therapeutic targets in core-binding factor AML (CBF-AML).

Main Methods:

  • Analysis of PU.1 gene regulation using alternative promoters and antisense transcription.
  • Investigating the role of RUNX transcription factors and CBF fusions (RUNX1-ETO, CBFβ-MYH11) in activating the PU.1 antisense promoter.
  • Comparing antisense/sense transcript ratios and promoter accessibility in CBF-AML patients, normal karyotype AML, and healthy cells.
  • Studying enhancer-promoter interactions to understand gene expression switching.

Main Results:

  • Transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3, induced by RUNX factors driving antisense transcription.
  • CBF fusions in t(8;21) and inv(16) AML activate the PU.1 antisense promoter, shifting transcription towards antisense and blocking myeloid differentiation.
  • Elevated antisense/sense transcript and promoter accessibility ratios are characteristic of CBF-AML patients.
  • A competitive interaction between an enhancer and promoters acts as a switch for myeloid or T-cell development.

Conclusions:

  • Leukemic CBF fusions hijack a physiological sense/antisense promoter competition mechanism to perturb gene expression.
  • This study reveals a novel mechanism of oncogene-induced gene expression alteration via promoter competition.
  • The findings identify a previously unrecognized Achilles' heel for targeted therapies in oncogene-induced chromatin remodeling in AML.