CURCUMIN AS A NOVEL EPIGENETIC TREATMENT APPROACH FOR GFI1-ASSOCIATED MDS/AML

Abstract

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are diseases caused by an ineffective myelopoiesis. AML is an aggressive blood cancer with poor prognosis for patients despite treatment with intensive chemotherapy, hence alternative therapies are needed. MDS and AML patients with low expression of the transcriptional repressor GFI1 (Growth factor independence 1) or expression of the GFI1 variant GFI1-36N (asparagine instead of serine at amino acid position 36) in their blast cells have an even poorer prognosis. GFI1 recruits amongst others HDAC1 and 2 (histone deacetylase 1 and 2) to its target genes. On a molecular level, expression of GFI1 thus leads to the removal of acetyl groups at H3K9. Low GFI1 (GFI1-KD) or GFI1-36N expression in MDS and AML blasts resulted in increased H3K9ac at its target genes, causing elevated target gene expression. Some of these target genes were oncogenes, explaining why GFI1-KD and GFI1-36N promote AML development. We hypothesized that administration of HAT (histone acetyltransferase) inhibitors could be beneficial for MDS/AML patients with reduced GFI1 or GFI1-36N expression as it could reverse the increased acetylation of H3K9. Curcumin is a HAT inhibitor which is used as a spice with so far no known toxic side effects. To study the effect of Curcumin on MDS/AML development, we crossed the well-established murine model of human MDS/AML, NUP98-HOXD13, with GFI1-WT, GFI1-KD or GFI1-36N mice. The different groups were treated with either curcumin or were left untreated. Curcumin effectively prevented the development of AML in mice with low GFI1 or GFI1-36N expression, but not in GFI1-WT mice. Overall, our data suggest that GFI1 functions as a prognostic marker in MDS/AML patients, resulting in a personalized treatment approach using Curcumin in patients with low GFI1 or GFI1-36N expression.