GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1

Velinder, Matthew; Singer, Jason; Bareyan, Diana; Meznarich, Jessica; Tracy, Christopher M.; Fulcher, James; McClellan, David; Lucente, Helena; Franklin, Sarah; Sharma, Sunil; Engel, Michael

doi:10.1042/bcj20160558

Cited by 34 publications

(25 citation statements)

References 37 publications

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“…Previous work and our own data has shown, that overexpression of GFI1 does not interfere with the viability of the haematopoietic system and hence targeting GFI1 levels could be a gateway to a novel therapy 37 . Future work has to examine whether a specific GFI1 degrading pathway or signalling cascades can be targeted to enhance activity of GFI1 as current data hint to this point 38 .…”

Section: Discussionmentioning

confidence: 99%

Enforced GFI1 expression impedes human and murine leukemic cell growth

Hönes

Thivakaran²,

Botezatu³

et al. 2017

Sci Rep

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The differentiation of haematopoietic cells is regulated by a plethora of so-called transcription factors (TFs). Mutations in genes encoding TFs or graded reduction in their expression levels can induce the development of various malignant diseases such as acute myeloid leukaemia (AML). Growth Factor Independence 1 (GFI1) is a transcriptional repressor with key roles in haematopoiesis, including regulating self-renewal of haematopoietic stem cells (HSCs) as well as myeloid and lymphoid differentiation. Analysis of AML patients and different AML mouse models with reduced GFI1 gene expression levels revealed a direct link between low GFI1 protein level and accelerated AML development and inferior prognosis. Here, we report that upregulated expression of GFI1 in several widely used leukemic cell lines inhibits their growth and decreases the ability to generate colonies in vitro. Similarly, elevated expression of GFI1 impedes the in vitro expansion of murine pre-leukemic cells. Using a humanized AML model, we demonstrate that upregulation of GFI1 expression leads to myeloid differentiation morphologically and immunophenotypically, increased level of apoptosis and reduction in number of cKit+ cells. These results suggest that increasing GFI1 level in leukemic cells with low GFI1 expression level could be a therapeutic approach.

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Section: Discussionmentioning

confidence: 99%

Enforced GFI1 expression impedes human and murine leukemic cell growth

Hönes

Thivakaran²,

Botezatu³

et al. 2017

Sci Rep

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show abstract

“…This implies that the chemoprobe cannot bind to KDM1A when the active site of the protein is occupied by GFI1 ( Figure 3C) and that chemoprobe and SNAG domain protein binding to KDM1A is mutually exclusive. Indeed, GFI1, GFI1B, and SNAI1 (Baron et al, 2011;Lin et al, 2010) have been described to mimic the histone tail and bind the amine oxidase domain of KDM1A via their (methylated) SNAG domains (Laurent et al, 2012;Velinder et al, 2016). CTBP1 does not itself contain a SNAG domain, but has been described to interact with proteins that do (Kuppuswamy et al, 2008).…”

Section: Chemoproteomics-based Profiling Of Kdm1a Protein-protein Intmentioning

confidence: 99%

ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia

et al. 2018

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The lysine-specific demethylase KDM1A is a key regulator of stem cell potential in acute myeloid leukemia (AML). ORY-1001 is a highly potent and selective KDM1A inhibitor that induces H3K4me2 accumulation on KDM1A target genes, blast differentiation, and reduction of leukemic stem cell capacity in AML. ORY-1001 exhibits potent synergy with standard-of-care drugs and selective epigenetic inhibitors, reduces growth of an AML xenograft model, and extends survival in a mouse PDX (patient-derived xenograft) model of T cell acute leukemia. Surrogate pharmacodynamic biomarkers developed based on expression changes in leukemia cell lines were translated to samples from patients treated with ORY-1001. ORY-1001 is a selective KDM1A inhibitor in clinical trials and is currently being evaluated in patients with leukemia and solid tumors.

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“…Importantly, knockdown of Gfi1 after MM exposure of murine pre‐OB or in patient‐derived MM‐BMSCs could reverse the OB suppression and enhanced response to OB differentiation signals. Transcriptional repression by Gfi1 is dependent on its recruitment of histone‐modifying enzymes histone deacetylase 1 (HDAC1), lysine‐specific histone demethylase 1 (LSD1/KDM1A), methyltransferase G9a, and EZH2 to target gene promoters . The first evidence of Gfi1‐mediated chromatin suppression of RUNX2 in the realm of myeloma suppression came from an experiment showing that overexpression of Gfi1 in preOBs inhibited RUNX2 reporter expression, and this was prevented by treatment with the HDAC inhibitor Trichostatin A .…”

Section: Chromatin Alterations In Mm‐exposed Bmscsmentioning

confidence: 99%

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

2019

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Multiple myeloma (MM) bone disease is characterized by the development of osteolytic lesions, which cause severe complications affecting the morbidity, mortality, and treatment of myeloma patients. Myeloma tumors seeded within the bone microenvironment promote hyperactivation of osteoclasts and suppression of osteoblast differentiation. Because of this prolonged suppression of bone marrow stromal cells’ (BMSCs) differentiation into functioning osteoblasts, bone lesions in patients persist even in the absence of active disease. Current antiresorptive therapy provides insufficient bone anabolic effects to reliably repair MM lesions. It has become widely accepted that myeloma‐exposed BMSCs have an altered phenotype with pro‐inflammatory, immune‐modulatory, anti‐osteogenic, and pro‐adipogenic properties. In this review, we focus on the role of epigenetic‐based modalities in the establishment and maintenance of myeloma‐induced suppression of osteogenic commitment of BMSCs. We will focus on recent studies demonstrating the involvement of chromatin‐modifying enzymes in transcriptional repression of osteogenic genes in MM‐BMSCs. We will further address the epigenetic plasticity in the differentiation commitment of osteoprogenitor cells and assess the involvement of chromatin modifiers in MSC‐lineage switching from osteogenic to adipogenic in the context of the inflammatory myeloma microenvironment. Lastly, we will discuss the potential of employing small molecule epigenetic inhibitors currently used in the MM research as therapeutics and bone anabolic agents in the prevention or repair of osteolytic lesions in MM. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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GFI1 functions in transcriptional control and cell fate determination require SNAG domain methylation to recruit LSD1

Cited by 34 publications

References 37 publications

Enforced GFI1 expression impedes human and murine leukemic cell growth

Enforced GFI1 expression impedes human and murine leukemic cell growth

ORY-1001, a Potent and Selective Covalent KDM1A Inhibitor, for the Treatment of Acute Leukemia

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

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