Recruitment of the Histone Methyltransferase SUV39H1 and Its Role in the Oncogenic Properties of the Leukemia-Associated PML-Retinoic Acid Receptor Fusion Protein

Abstract

Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

“…Indeed, the involvement of HMTs recruited to regulate the transcription of hematopoietic genes such as EVI-1, AML1 and PML-RARa during leukemogenesis would be in favor of the use of an HMT-targeted therapy. [40][41][42] In support of the HMT-based therapy, aberrant gene silencing results from increased SUV39H1 occupancy of target promoter regions. 23 SUV39H1 downregulation inhibits the colony formation activity of EVI-1-expressing cells, underlining a role for SUV39H1 in EVI-1-mediated bone marrow immortalization and leukemogenesis.…”

TLS-ERG Leukemia Fusion Protein Deregulates Cyclin-Dependent Kinase 1 and Blocks Terminal Differentiation of Myeloid Progenitor Cells

“…Silencing of genes critical to myeloid differentiation is a well-known phenomenon associated with leukemia fusion proteins. The most notable case involves acute promyelocytic leukemia in which a t(15;17) translocation fuses PML protein with the retinoic acid receptor-a, and gene repression by the resultant PML-RARa can be reversed by treatment with all-trans retinoic acid (11).…”

The self-association coiled-coil domain of PML is sufficient for the oncogenic conversion of the retinoic acid receptor (RAR) alpha

“…3,4 Less frequent partners involved in the APL-related translocations comprise promyelocytic leukemia zinc-finger gene, 5 nucleophosmin, 6 nuclear mitotic apparatus 7 and signal transducer and activator of transcription 5b. 8 The oncogenic PML-RARa (PR) fusion protein behaves as an altered RAR, with an expanded repertoire of DNA-binding sites, 9 and acts as a constitutive repressor of retinoic acid (RA) target genes because of an aberrant recruitment of chromatin modifying enzymes (that is, histone deacetylases, 10,11 histone methyltransferases 12 and DNA methyltransferases 13 ). These chromatin changes subvert the normal gene expression pattern thus altering cell transcriptional state and enhancing the self-renewal property of PR-expressing cells.…”