de Groot Anne P, Nguyen Huong, Pouw Jacobine S, Weersing Ellen, Dethmers-Ausema Albertina, de Haan Gerald
European Research Institute for Biology of Ageing (ERIBA), University Medical Center Groningen, Groningen, The Netherlands; Sanquin Research, Amsterdam, the Netherlands.
European Research Institute for Biology of Ageing (ERIBA), University Medical Center Groningen, Groningen, The Netherlands.
Exp Hematol. 2025 Feb;142:104691. doi: 10.1016/j.exphem.2024.104691. Epub 2024 Nov 28.
The epigenome of leukemic cells is dysregulated, and genes required for cell cycle arrest and differentiation may become repressed, which contributes to the accumulation of undifferentiated malignant blood cells. Here, we show that the Polycomb group protein CBX7 can interact with H3K9 methyltransferases EHMT1/2 and SETDB1. We aimed to assess whether combined interfering with these H3K9 methyltransferases and CBX7 could derepress target genes and thereby induce growth arrest of leukemic cells. We found that pharmacologic inhibition of CBX7 abolishes the interaction of CBX7 with EHMT1/2 and SETDB1 and subsequently reduces H3K9 methylation levels which reactivates target gene expression. Reversely, upon pharmacologic inhibition of H3K9 methyltransferases, CBX7 can take over gene repression. Finally, we found that combined inhibition of CBX7 and EHMT1/2 or SETDB1 had additive effects on reducing cell growth and inducing differentiation. However, we did not detect changes in epigenetic modifications, nor target gene derepression, after combination treatment. In contrast, CBX7 inhibitors alone did affect both Polycomb-associated H2Aub-mediated gene repression as well as H3K9 methyltransferase activity. Therefore, we suggest that CBX7 is a promising therapeutic target in leukemia, as its inhibition can reactivate Polycomb and H3K9 methyltransferase target gene expression.
白血病细胞的表观基因组失调，细胞周期停滞和分化所需的基因可能会被抑制，这导致未分化恶性血细胞的积累。在此，我们表明多梳蛋白家族蛋白CBX7可与H3K9甲基转移酶EHMT1/2和SETDB1相互作用。我们旨在评估联合干扰这些H3K9甲基转移酶和CBX7是否能解除对靶基因的抑制，从而诱导白血病细胞生长停滞。我们发现，对CBX7的药理抑制消除了CBX7与EHMT1/2和SETDB1的相互作用，随后降低了H3K9甲基化水平，从而重新激活了靶基因表达。相反，在对H3K9甲基转移酶进行药理抑制后，CBX7可接管基因抑制作用。最后，我们发现联合抑制CBX7和EHMT1/2或SETDB1对降低细胞生长和诱导分化具有累加效应。然而，联合治疗后，我们未检测到表观遗传修饰的变化，也未检测到靶基因抑制的解除。相比之下，单独使用CBX7抑制剂确实会影响多梳相关的H2Aub介导的基因抑制以及H3K9甲基转移酶活性。因此，我们认为CBX7是白血病中一个有前景的治疗靶点，因为对其抑制可重新激活多梳蛋白和H3K9甲基转移酶靶基因的表达。
