Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications

Abstract

Growth factor independence 1 (GFI1) is a DNA binding zinc finger protein, which can mediate transcriptional repression mainly by recruiting histone-modifying enzymes to its target genes. GFI1 plays important roles in hematopoiesis, in particular by regulating both the function of hematopoietic stem- and precursor cells and differentiation along myeloid and lymphoid lineages. In recent years, a number of publications have provided evidence that GFI1 is involved in the pathogenesis of acute myeloid leukemia (AML), its proposed precursor, myelodysplastic syndrome (MDS), and possibly also in the progression from MDS to AML. For instance, expression levels of the GFI1 gene correlate with patient survival and treatment response in both AML and MDS and can influence disease progression and maintenance in experimental animal models. Also, a non-synonymous single nucleotide polymorphism (SNP) of GFI1, GFI1 -36N, which encodes a variant GFI1 protein with a decreased efficiency to act as a transcriptional repressor, was found to be a prognostic factor for the development of AML and MDS. Both the GFI1 -36N variant as well as reduced expression of the GFI1 gene lead to genome-wide epigenetic changes at sites where GFI1 occupies target gene promoters and enhancers. These epigenetic changes alter the response of leukemic cells to epigenetic drugs such as HDAC- or HAT inhibitors, indicating that GFI1 expression levels and genetic variants of GFI1 are of clinical relevance. Based on these and other findings, specific therapeutic approaches have been proposed to treat AML by targeting some of the epigenetic changes that occur as a consequence of GFI1 expression. Here, we will review the well-known role of Gfi1 as a transcription factor and describe the more recently discovered functions of GFI1 that are independent of DNA binding and how these might affect disease progression and the choice of epigenetic drugs for therapeutic regimens of AML and MDS.

Cadmium, Smoking, and Human Blood DNA Methylation Profiles in Adults from the Strong Heart Study

“…Moreover, the F2RL3 gene, which encodes a protease-activated receptor that plays a role in blood coagulation, inflammation, response to pain, and cancer, is also highly connected in the network and directly interacts with RARA, which has been associated with increased sensitivity to retinoids in T-cell lymphoma in experimental settings (Wang et al 2017). Other highly connected smoking-DMPs in the network, such as MYO1G, GFI1, CDKN1A, GNG12, and CYP1B1, have been previously reported as smoking-DMPs in other epigenetic studies (Gonseth et al 2016;Steenaard et al 2015;Stueve et al 2017;Wiklund et al 2019) and have also been implicated in cancer (Groth-Pedersen et al 2012;Möröy and Khandanpour 2019;Yao et al 2018) or cardiometabolic diseases (Dempsie et al 2013;Parmar et al 2018). All of them are directly connected to Cd-associated nodes.…”

Epigenetic Regulations of AhR in the Aspect of Immunomodulation

“…Another transcriptional factor that has an impact on chromatin architecture is growth factor independence (GFI1). It has been shown that GFI1 mediates transcriptional repression mainly by recruiting histone-modifying enzymes such as histone deacetylases (HDAC-1–3), histone methyltransferases (EHMT2) or histone demethylases (KDM1A/LSD1/) [ 169 ]. GFI1 promoted the development of gut innates lymphocyte (ILC2).…”

Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

“…LSD1i treatment also increased chromatin accessibility and binding of SPI1 and CEBPα at their target Es/promoters 28 . Knockdown by shRNA or treatment with either the irreversible tranylcypromine (TCP)-derivative LSD1i or the reversible LSD1i SP2509 disrupted LSD1-binding to CoREST and GFI1/1B, induce differentiation markers (CD86 and CD11b) and morphologic differentiation, repress colony growth, as well as sensitize AML blast progenitor cells (BPCs) to all-trans retinoic acid (ATRA) 23 , 25 , 29 – 32 . Co-treatment with LSD1i and cytarabine, DNA hypomethylating agents, or inhibitor of HDACs, FLT3, DOT1L or BCL2, was shown to exert synergistic lethality in AML expressing MLL fusion protein 25 , 30 .…”