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EZH2 inhibitor GSK126 promotes human iPSC hematopoietic differentiation

ABSTRACT: The de novo generation of human hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) represents a promising avenue for the cellular therapy of blood disorders. However, existing protocols often result in the production of immature progenitors with limited multilineage engraftment capacity in vivo. This limitation is believed to be due to an epigenetic barrier, particularly involving the Polycomb Repressor Complex 2 (PRC2), which mediates transcriptional repression during hematopoietic development through H3K27me3 methylation. In this study, we explored the suppression of EZH2, a key component of PRC2, using the small molecule inhibitor GSK126 at various stages of iPSC differentiation. Our findings revealed that EZH2 inhibition leads to an increase in phenotypic HSCs and enhances long-term colony-forming unit (CFU) colony formation. Single-cell RNA sequencing further demonstrated that GSK126 promotes iPSC hematopoietic differentiation. These results highlight the potential of EZH2 inhibition to overcome epigenetic barriers and enhance iPSC-derived hematopoietic differentiation, paving the way for advancements in regenerative medicine and transplantation therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342748 | GEO | 2026/08/10

REPOSITORIES: GEO

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Project description:We studied transcriptional changes by Affymetrix human microarrays in DLBCL cell lines as a result of treatment with GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 In eukaryotes, epigenetic post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is responsible for repressing target gene expression through methylation of histone H3 on lysine 27 (H3K27). Over-expression of EZH2 is implicated in tumorigenesis and correlates with poor prognosis in multiple tumor types. Recent reports have identified somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). The Y641 residue is the most frequently mutated residue, with 22% of GCB (Germinal Cell B-cell) DLBCL and FL harboring mutations at this site. These lymphomas exhibit increased H3K27 tri-methylation (H3K27me3) due to altered substrate preferences of the mutant enzymes. However, it is unknown whether direct inhibition of EZH2 methyltransferase activity alone will be effective in treating lymphomas carrying activating EZH2 mutations. Herein, we demonstrate that GSK126, a potent, highly-selective, SAM-competitive, small molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and dramatically inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma. 10 DLBCL cell lines (7 mutant and 3 wild type EZH2), that were differentially sensitive to GSK126 in proliferation assays, were treated for 72 hours, in duplicate (n=2), with either DMSO (vehicle) or 500nM of GSK126, a potent selective EZH2 inhibitor. EZH2 mutant cell lines are Pfeiffer, KARPAS-422, WSU-DLCL2, SU-DHL-10, SU-DHL-6, DB and SU-DHL-4. EZH2 wildtype cell lines are HT, OCI-LY-19 and Toledo.

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EZH2 inhibitor GSK126 promotes human iPSC hematopoietic differentiation

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