Targeted epigenetic repression of a lymphoma oncogene by sequence-specific histone modifiers induces apoptosis in DLBCL.
Alterations to the epigenetic landscape of diffuse large B-cell lymphoma (DLBCL) play a fundamental role in deregulating genes involved in normal lymphocyte differentiation. To determine whether targeted epigenetic therapy could reverse these pathogenic chromatin changes and suppress the expression of a lymphoma oncogene, we focused on BCL6, a transcriptional repressor whose aberrant expression is tightly linked to DLBCL proliferation and survival. We fused zinc-finger (ZF) domains specific for regulatory regions in the BCL6 locus to a repressive epigenetic modifier, the Kruppel-associated box (KRAB) repressor domain. Distinct ZF-KRAB fusions repressed the local chromatin landscape, suppressed BCL6 expression, significantly impaired DLBCL growth, and caused widespread cell death in a BCL6-dependent manner. Importantly, expression of ectopic BCL6 protein rescued ZF-KRAB-induced cell death, demonstrating the modifiers' specificity. We show that sequence-specific epigenetic modifiers can alter oncogene expression and induce apoptosis in cancer cells, underscoring their potential for future development as targeted epigenetic protein therapies.
a Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
Hong
H
Luo
a Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
Jennifer A
JA
Schmidt
a Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
Yi-Shan
YS
Lee
a Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
Eugene M
EM
Oltz
a Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA.
Jacqueline E
JE
Payton
D017209:Apoptosis / Q000235:genetics*; D001665:Binding Sites; D000066630:Ectopic Gene Expression; D063185:Epigenetic Repression; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D006657:Histones / Q000378:metabolism*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
C084103:BCL6 protein, human; D006657:Histones; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins
Chemotherapeutic approaches; lymphoma and Hodgkin disease; transcription factor changes