Faculty Collaboration Database

Core-binding factor leukemia hijacks the T-cell-prone PU.1 antisense promoter. Blood 2021 Oct 14;138(15):1345-1358

Date

05/20/2021

Pubmed ID

34010414

Pubmed Central ID

PMC8525333

DOI

10.1182/blood.2020008971

Scopus ID

2-s2.0-85112289640 (requires institutional sign-in at Scopus site)   9 Citations

Abstract

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

Author List

van der Kouwe E, Heller G, Czibere A, Pulikkan JA, Agreiter C, Castilla LH, Delwel R, Di Ruscio A, Ebralidze AK, Forte M, Grebien F, Heyes E, Kazianka L, Klinger J, Kornauth C, Le T, Lind K, Barbosa IAM, Pemovska T, Pichler A, Schmolke AS, Schweicker CM, Sill H, Sperr WR, Spittler A, Surapally S, Trinh BQ, Valent P, Vanura K, Welner RS, Zuber J, Tenen DG, Staber PB

Author

John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antisense Elements (Genetics)
Cell Line, Tumor
Core Binding Factor Alpha 2 Subunit
Core Binding Factor beta Subunit
Gene Expression Regulation, Leukemic
Gene Fusion
Humans
Leukemia, Myeloid, Acute
Oncogene Proteins, Fusion
Promoter Regions, Genetic
Proto-Oncogene Proteins
RUNX1 Translocation Partner 1 Protein
Trans-Activators
Tumor Cells, Cultured