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Tarik Moroy - One of the best experts on this subject based on the ideXlab platform.
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multifaceted actions of GFI1 and GFI1b in hematopoietic stem cell self renewal and lineage commitment
Frontiers in Genetics, 2020Co-Authors: Hugues Beauchemin, Tarik MoroyAbstract:Growth factor independence 1 (GFI1) and the closely related protein GFI1B are small nuclear proteins that act as DNA binding transcriptional repressors. Both recognize the same consensus DNA binding motif via their C-terminal zinc finger domains and regulate the expression of their target genes by recruiting chromatin modifiers such as histone deacetylases (HDACs) and demethylases (LSD1) by using an N-terminal SNAG domain that comprises only 20 amino acids. The only region that is different between both proteins is the region that separates the zinc finger domains and the SNAG domain. Both proteins are co-expressed in hematopoietic stem cells (HSCs) and, to some extent, in multipotent progenitors (MPPs), but expression is specified as soon as early progenitors and show signs of lineage bias. While expression of GFI1 is maintained in lymphoid primed multipotent progenitors (LMPPs) that have the potential to differentiate into both myeloid and lymphoid cells, GFI1B expression is no longer detectable in these cells. By contrast, GFI1 expression is lost in megakaryocyte precursors (MKPs) and in megakaryocyte-erythrocyte progenitors (MEPs), which maintain a high level of GFI1B expression. Consequently, GFI1 drives myeloid and lymphoid differentiation and GFI1B drives the development of megakaryocytes, platelets, and erythrocytes. How such complementary cell type- and lineage-specific functions of GFI1 and GFI1B are maintained is still an unresolved question in particular since they share an almost identical structure and very similar biochemical modes of actions. The cell type-specific accessibility of GFI1/1B binding sites may explain the fact that very similar transcription factors can be responsible for very different transcriptional programming. An additional explanation comes from recent data showing that both proteins may have additional non-transcriptional functions. GFI1 interacts with a number of proteins involved in DNA repair and lack of GFI1 renders HSCs highly susceptible to DNA damage-induced death and restricts their proliferation. In contrast, GFI1B binds to proteins of the beta-catenin/Wnt signaling pathway and lack of GFI1B leads to an expansion of HSCs and MKPs, illustrating the different impact that GFI1 or GFI1B has on HSCs. In addition, GFI1 and GFI1B are required for endothelial cells to become the first blood cells during early murine development and are among those transcription factors needed to convert adult endothelial cells or fibroblasts into HSCs. This role of GFI1 and GFI1B bears high significance for the ongoing effort to generate hematopoietic stem and progenitor cells de novo for the autologous treatment of blood disorders such as leukemia and lymphoma.
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Multifaceted Actions of GFI1 and GFI1B in Hematopoietic Stem Cell Self-Renewal and Lineage Commitment
Frontiers in genetics, 2020Co-Authors: Hugues Beauchemin, Tarik MoroyAbstract:Growth factor independence 1 (GFI1) and the closely related protein GFI1B are small nuclear proteins that act as DNA binding transcriptional repressors. Both recognize the same consensus DNA binding motif via their C-terminal zinc finger domains and regulate the expression of their target genes by recruiting chromatin modifiers such as histone deacetylases (HDACs) and demethylases (LSD1) through an N-terminal SNAG domain that comprises only 20 amino acids. The only region that is different between both proteins is the region that separates the zinc finger domains and the SNAG domain. Both proteins are co-expressed in hematopoietic stem cells (HSCs) and to some extent in multipotent progenitors (MPPS), but expression is specified as soon as early progenitors show signs of lineage bias. While expression of GFI1 is maintained in LMPPs (lymphoid primed multipotent progenitors) that have the potential to differentiate into both myeloid and lymphoid cells, GFI1B expression is no longer detectable in these cells. By contrast, GFI1 expression is lost in megakaryocyte precursors (MKPs) and in megakaryocytic erythrocyte progenitors (MEPs), which maintain a high level of GFI1B expression. Consequently, GFI1 drives myeloid and lymphoid differentiation and GFI1B the development of megakaryocytes, platelets and erythrocytes. How such complementary cell type- and lineage specific functions of GFI1 and GFI1B are maintained is still an unresolved question in particular since they share an almost identical structure and very similar biochemical functions. The cell type specific accessibility of GFI1/B binding sites may offer an explanation, but also the fact that both proteins can have different, non-transcriptional functions where GFI1 controls the activity of DNA repair proteins and GFI1B regulates the Wnt/beta catenin signaling pathway. In addition, GFI1 and GFI1B are required for endothelial cells to become the first blood cells during early murine development and are among those transcription factors needed to convert adult endothelial cells or fibroblasts into hematopoietic stem cells. This role of GFI1 and GFI1B bears high significance for the ongoing effort to generate hematopoietic stem and -progenitor cells de novo for the autologous treatment of blood disorders such as leukemia and lymphoma.
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Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications.
Frontiers in oncology, 2019Co-Authors: Tarik Moroy, Cyrus KhandanpourAbstract: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.
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GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1
Nature Cell Biology, 2016Co-Authors: Roshana Thambyrajah, Rahima Patel, Christophe Lancrin, Monika Stefanska, Milena Mazan, Victoria Moignard, Elli Marinopoulou, Thomas Clapes, Yaoyong Li, Tarik MoroyAbstract:In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta–gonad–mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that GFI1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells. Lacaud and colleagues show that the GFI1 transcriptional repressors are required for endothelial-to-haematopoietic transition in the aorta–gonad–mesonephros region of the mouse embryo by inhibiting the endothelial gene expression program via LSD1.
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from cytopenia to leukemia the role of GFI1 and GFI1b in blood formation
Blood, 2015Co-Authors: Lothar Vassen, Tarik Moroy, Brian Wilkes, Cyrus KhandanpourAbstract:The DNA-binding zinc finger transcription factors GFI1 and GFI1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of GFI1 and GFI1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that GFI1 is primarily important in myeloid and lymphoid differentiation, whereas GFI1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the GFI1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of GFI1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.
Judith Schütte - One of the best experts on this subject based on the ideXlab platform.
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Curcumin as a Novel Epigenetic Treatment Approach for GFI1-Associated MDS/AML
Experimental Hematology, 2019Co-Authors: Judith Schütte, Aniththa Thivakaran, Pradeep Patnana, Yahya S. Al-matary, Lothar Vassen, Ulrich Dührsen, Daria Frank, Dennis Heinrichs, Marina Suslo, Cyrus KhandanpourAbstract: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.
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curcumin as a novel epigenetic treatment approach for GFI1 associated mds aml
Experimental Hematology, 2018Co-Authors: Judith Schütte, Aniththa Thivakaran, Pradeep Patnana, Ulrich Dührsen, Daria Frank, Dennis Heinrichs, Marina Suslo, Yahya Saleh Almatary, Lothar Vasen, Cyrus KhandanpourAbstract: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.
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Enforced GFI1 expression impedes human and murine leukemic cell growth
Scientific Reports, 2017Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, Pradeep Patnana, Symone Vitoriano Da Conceição Castro, Yahya S. Al-matary, Karen B. I. Fischer, Lothar Vassen, Judith Schütte, André GörgensAbstract: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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GFI1 as a novel prognostic and therapeutic factor for AML/MDS
Leukemia, 2016Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, S M Hergenhan, Lothar Vassen, Carolyn Vadnais, Judith Schütte, Anne Helness, F Robert, Yahya S. Al-mataryAbstract:Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression ( GFI1-KD ). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
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GFI1 as a novel prognostic and therapeutic factor for aml mds
Leukemia, 2016Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, S M Hergenhan, Lothar Vassen, Carolyn Vadnais, Judith Schütte, Anne Helness, F Robert, Yahya Saleh AlmataryAbstract:Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
Cyrus Khandanpour - One of the best experts on this subject based on the ideXlab platform.
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Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications.
Frontiers in oncology, 2019Co-Authors: Tarik Moroy, Cyrus KhandanpourAbstract: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.
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Dose-dependent role of GFI1 in murine hematopoietic stem cell self-renewal and differentiation
2019Co-Authors: Judith Schuette, Aniththa Thivakaran, Pradeep Patnana, Yahya S. Al-matary, Daria Frank, Daniel R Engel, Ulrich Duehrsen, Cyrus KhandanpourAbstract:GFI1 (Growth factor independence 1) is a transcription factor that influences the stem cell capacity of hematopoietic stem cells (HSCs) as well as their differentiation into the myeloid and lymphoid lineage. Loss of GFI1 impedes the repopulation capacity of HSCs and leads to a block in granulocyte generation causing severe neutropenia and monocytosis. Competitive transplantation assays showed that GFI1-deficient cells were not able to reconstitute myeloid and lymphoid hematopoiesis in competition with GFI1-wildtype (GFI1-36S) cells. Low GFI1 levels (GFI1-knockdown = GFI1-KD) in blasts of myelodysplastic neoplasms, acute and chronic myeloid leukemia patients are associated with poor patient survival. To understand how reduced levels or loss of GFI1 contribute to hematopoiesis, we analyzed the effect of GFI1-KD and GFI1-KO on HSCs and more mature cell types in mice. GFI1-KD and GFI1-KO led to strong decrease in HSC numbers, while the numbers of early progenitors (Lin-Sca1+cKit+ cells) were slightly increased. Competitive transplantation assays showed that GFI1-KD and GFI1-KO HSCs can still engraft and expand, but they cannot contribute to myeloid and lymphoid differentiation.
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Curcumin as a Novel Epigenetic Treatment Approach for GFI1-Associated MDS/AML
Experimental Hematology, 2019Co-Authors: Judith Schütte, Aniththa Thivakaran, Pradeep Patnana, Yahya S. Al-matary, Lothar Vassen, Ulrich Dührsen, Daria Frank, Dennis Heinrichs, Marina Suslo, Cyrus KhandanpourAbstract: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.
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curcumin as a novel epigenetic treatment approach for GFI1 associated mds aml
Experimental Hematology, 2018Co-Authors: Judith Schütte, Aniththa Thivakaran, Pradeep Patnana, Ulrich Dührsen, Daria Frank, Dennis Heinrichs, Marina Suslo, Yahya Saleh Almatary, Lothar Vasen, Cyrus KhandanpourAbstract: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.
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GFI1 facilitates efficient DNA repair by regulating PRMT1 dependent methylation of MRE11 and 53BP1.
Nature communications, 2018Co-Authors: Charles Vadnais, Cyrus Khandanpour, Daria Frank, Riyan Chen, Jennifer Fraszczak, Jonathan Boulais, Jordan Pinder, Josée Hébert, Graham DellaireAbstract:GFI1 is a transcriptional regulator expressed in lymphoid cells, and an "oncorequisite" factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins. Specifically, GFI1 interacts with the arginine methyltransferase PRMT1 and its substrates MRE11 and 53BP1. We demonstrate that GFI1 enables PRMT1 to bind and methylate MRE11 and 53BP1, which is necessary for their function in the DNA damage response. Thus, our results provide evidence that GFI1 can adopt non-transcriptional roles, mediating the post-translational modification of proteins involved in DNA repair. These findings have direct implications for treatment responses in tumors overexpressing GFI1 and suggest that GFI1's activity may be a therapeutic target in these malignancies.
Lothar Vassen - One of the best experts on this subject based on the ideXlab platform.
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Curcumin as a Novel Epigenetic Treatment Approach for GFI1-Associated MDS/AML
Experimental Hematology, 2019Co-Authors: Judith Schütte, Aniththa Thivakaran, Pradeep Patnana, Yahya S. Al-matary, Lothar Vassen, Ulrich Dührsen, Daria Frank, Dennis Heinrichs, Marina Suslo, Cyrus KhandanpourAbstract: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.
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Enforced GFI1 expression impedes human and murine leukemic cell growth
Scientific Reports, 2017Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, Pradeep Patnana, Symone Vitoriano Da Conceição Castro, Yahya S. Al-matary, Karen B. I. Fischer, Lothar Vassen, Judith Schütte, André GörgensAbstract: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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GFI1 as a novel prognostic and therapeutic factor for AML/MDS
Leukemia, 2016Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, S M Hergenhan, Lothar Vassen, Carolyn Vadnais, Judith Schütte, Anne Helness, F Robert, Yahya S. Al-mataryAbstract:Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression ( GFI1-KD ). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
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GFI1 as a novel prognostic and therapeutic factor for aml mds
Leukemia, 2016Co-Authors: Judith M. Hönes, Aniththa Thivakaran, Lacramioara Botezatu, S M Hergenhan, Lothar Vassen, Carolyn Vadnais, Judith Schütte, Anne Helness, F Robert, Yahya Saleh AlmataryAbstract:Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.
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from cytopenia to leukemia the role of GFI1 and GFI1b in blood formation
Blood, 2015Co-Authors: Lothar Vassen, Tarik Moroy, Brian Wilkes, Cyrus KhandanpourAbstract:The DNA-binding zinc finger transcription factors GFI1 and GFI1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of GFI1 and GFI1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that GFI1 is primarily important in myeloid and lymphoid differentiation, whereas GFI1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the GFI1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of GFI1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.
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GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1
Nature Cell Biology, 2016Co-Authors: Roshana Thambyrajah, Rahima Patel, Christophe Lancrin, Monika Stefanska, Milena Mazan, Victoria Moignard, Elli Marinopoulou, Thomas Clapes, Yaoyong Li, Tarik MoroyAbstract:In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta–gonad–mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that GFI1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells. Lacaud and colleagues show that the GFI1 transcriptional repressors are required for endothelial-to-haematopoietic transition in the aorta–gonad–mesonephros region of the mouse embryo by inhibiting the endothelial gene expression program via LSD1.
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GFI1 proteins orchestrate the emergence of haematopoietic stem cells through recruitment of LSD1
Nature cell biology, 2015Co-Authors: Roshana Thambyrajah, Rahima Patel, Christophe Lancrin, Monika Stefanska, Milena Mazan, Victoria Moignard, Elli Marinopoulou, Thomas Clapes, Tarik MoroyAbstract:In vertebrates, the first haematopoietic stem cells (HSCs) with multi-lineage and long-term repopulating potential arise in the AGM (aorta-gonad-mesonephros) region. These HSCs are generated from a rare and transient subset of endothelial cells, called haemogenic endothelium (HE), through an endothelial-to-haematopoietic transition (EHT). Here, we establish the absolute requirement of the transcriptional repressors GFI1 and GFI1B (growth factor independence 1 and 1B) in this unique trans-differentiation process. We first demonstrate that GFI1 expression specifically defines the rare population of HE that generates emerging HSCs. We further establish that in the absence of GFI1 proteins, HSCs and haematopoietic progenitor cells are not produced in the AGM, revealing the critical requirement for GFI1 proteins in intra-embryonic EHT. Finally, we demonstrate that GFI1 proteins recruit the chromatin-modifying protein LSD1, a member of the CoREST repressive complex, to epigenetically silence the endothelial program in HE and allow the emergence of blood cells.
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characterization of transcriptional networks in blood stem and progenitor cells using high throughput single cell gene expression analysis
Nature Cell Biology, 2013Co-Authors: Victoria Moignard, Judith Schütte, Iain C Macaulay, Gemma Swiers, Florian Buettner, Fernando J Caleronieto, Sarah Kinston, Anagha Joshi, Rebecca Hannah, Fabian J TheisAbstract:Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterized by distinctive transcription factor expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated transcription factor pairings, including previously unrecognized relationships between Gata2, GFI1 and GFI1b. Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between GFI1 and GFI1b. Single-cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.
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Characterization of transcriptional networks in blood stem and progenitor cells using high-throughput single-cell gene expression analysis
Nature Cell Biology, 2013Co-Authors: Victoria Moignard, Judith Schütte, Iain C Macaulay, Gemma Swiers, Florian Buettner, Sarah Kinston, Anagha Joshi, Rebecca Hannah, Fernando J. Calero-nieto, Fabian J TheisAbstract:Gottgens and colleagues have analysed the expression of 18 haematopoietic factors in single primary blood and progenitor cells from mouse bone marrow. They delineate distinct states of expression for these transcription factors and identify regulatory relationships between the key factors Gata2, GFI1 and Gfi2. Cellular decision-making is mediated by a complex interplay of external stimuli with the intracellular environment, in particular transcription factor regulatory networks. Here we have determined the expression of a network of 18 key haematopoietic transcription factors in 597 single primary blood stem and progenitor cells isolated from mouse bone marrow. We demonstrate that different stem/progenitor populations are characterized by distinctive transcription factor expression states, and through comprehensive bioinformatic analysis reveal positively and negatively correlated transcription factor pairings, including previously unrecognized relationships between Gata2 , GFI1 and GFI1b . Validation using transcriptional and transgenic assays confirmed direct regulatory interactions consistent with a regulatory triad in immature blood stem cells, where Gata2 may function to modulate cross-inhibition between GFI1 and GFI1b . Single-cell expression profiling therefore identifies network states and allows reconstruction of network hierarchies involved in controlling stem cell fate choices, and provides a blueprint for studying both normal development and human disease.