Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS).

Xiaoqing Xie,Longlong Liu,Judith Schütte,Daria Frank,Julian Varghese,Lanying Wei,Yahya Al-Matary,Pradeep Kumar Patnana,Cyrus Khandanpour,Subbaiah Chary Nimmagadda,Martin Dugas

doi:10.3390/ijms23010411

Abstract

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or –KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

Highlights

Acute myeloid leukaemia (AML) is the most common myeloid leukaemia in adults characterized by an accumulation of immature myeloid cells [1,2]
We have earlier reported that a lower expression of Growth Factor Independence 1 (GFI1) or the expression of its single nucleotide polymorphism (SNP) variant, promoted the progression of Myelodysplastic Syndrome (MDS) to AML in the murine model of MDS/AML, NUP98-HOXD13 [1,6,14]
As compared with the GFI1-36S murine model, GFI1-36N or lower expression resulted in increased H3K9 acetylation of the regulatory elements of GFI1 target genes and contributed to the progression of MDS to AML [7]

Summary

Introduction

Acute myeloid leukaemia (AML) is the most common myeloid leukaemia in adults characterized by an accumulation of immature myeloid cells [1,2]. Myelodysplastic Syndrome (MDS), another disease of myeloid origin is characterized by the perturbed function of the myeloid-erythroid-megakaryocytic lineage resulting in neutropenia, thrombocytopenia and anaemia [3]. Murine studies have identified an important role for Gfi in the quiescence of HSCs and their differentiation into cells of myeloid and lymphoid lineages [5]. We generated various murine strains characterized by lower GFI1 expression or those expressing cDNA of full-length human GFI1-36S or -36N in murine locus and demonstrated their role in MDS and AML [6,13,14]. The mouse models elucidated an important role for reduced Gfi expression and the expression of GFI1-36N SNP variant in the accelerated onset of fatal myeloid proliferative disease (MPS) and increased the risk for AML progression [6,7,14,15]

Methods

Results

Conclusion