GFI1; growth factor independent 1 transcription repressor (1p22)

Gene Summary

Gene:GFI1; growth factor independent 1 transcription repressor
Aliases: SCN2, GFI-1, GFI1A, ZNF163
Summary:This gene encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including hematopoiesis and oncogenesis. It functions as part of a complex along with other cofactors to control histone modifications that lead to silencing of the target gene promoters. Mutations in this gene cause autosomal dominant severe congenital neutropenia, and also dominant nonimmune chronic idiopathic neutropenia of adults, which are heterogeneous hematopoietic disorders that cause predispositions to leukemias and infections. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:zinc finger protein Gfi-1
Updated:14 December, 2014


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (1)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
LeukaemiaGFI1 and Leukaemia View Publications25

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: GFI1 (cancer-related)

Chen J, Weiss WA
When deletions gain functions: commandeering epigenetic mechanisms.
Cancer Cell. 2014; 26(2):160-1 [PubMed] Article available free on PMC after 11/08/2015 Related Publications
Recurrent chromosomal deletions in cancer are typically thought to harbor tumor suppressors. In a recent publication in Nature, Northcott and colleagues identify a novel region of structural variation in medulloblastoma that leads to oncogenic activation of GFI1B and GFI1 by repositioning these genes next to super-enhancers.

Related: Childhood Medulloblastoma / PNET

Inoue T, Swain A, Nakanishi Y, Sugiyama D
Multicolor analysis of cell surface marker of human leukemia cell lines using flow cytometry.
Anticancer Res. 2014; 34(8):4539-50 [PubMed] Related Publications
BACKGROUND: Leukemia cell lines are utilized as tools for molecular analysis. Their implementation in therapy will require standards for quality control, including appropriate selection criteria for functional analysis and efficacy determination.
MATERIALS AND METHODS: Characteristics of six human leukemia cell lines -Kasumi-1, NB-4, MOLM-13, MV-4-11, K562, and Jurkat cells-were investigated using multiple color analysis of surface antigen expression and comparative analysis of gene expression.
RESULTS: Differentiation states of Kasumi-1 and MOLM-13 cells are colony-forming units-granulocyte/macrophage equivalent cells to myeloblasts with comparatively high Growth factor independent-1(GFI1) and Transcription factor PU.1 (PU.1) expression, respectively. NB4 and MV-4-11 express high levels of CCAAT/enhancer-binding protein-alpha (CEBPα) and differentiate from myeloblasts to pro-monocytes and myeloblasts, respectively. K562 cells are colony-forming units-erythroid equivalent cells to erythroblasts, with the highest expression of GATA-binding factor 2 (GATA2), GATA1 and Friend of gata-1 (FOG1). Jurkat cells are pro-T to mature T-cells with the highest Neurogenic locus notch-1 homolog protein 1 (NOTCH1) expression.
CONCLUSION: Our study gives a useful guideline of standards for appropriate usage of leukemia cell lines for examining novel targets in vitro.

Related: Leukemia

Northcott PA, Lee C, Zichner T, et al.
Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
Nature. 2014; 511(7510):428-34 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.

Related: Chromosome 9 Childhood Medulloblastoma / PNET

Velu CS, Chaubey A, Phelan JD, et al.
Therapeutic antagonists of microRNAs deplete leukemia-initiating cell activity.
J Clin Invest. 2014; 124(1):222-36 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Acute myelogenous leukemia (AML) subtypes that result from oncogenic activation of homeobox (HOX) transcription factors are associated with poor prognosis. The HOXA9 transcription activator and growth factor independent 1 (GFI1) transcriptional repressor compete for occupancy at DNA-binding sites for the regulation of common target genes. We exploited this HOXA9 versus GFI1 antagonism to identify the genes encoding microRNA-21 and microRNA-196b as transcriptional targets of HOX-based leukemia oncoproteins. Therapeutic inhibition of microRNA-21 and microRNA-196b inhibited in vitro leukemic colony forming activity and depleted in vivo leukemia-initiating cell activity of HOX-based leukemias, which led to leukemia-free survival in a murine AML model and delayed disease onset in xenograft models. These data establish microRNA as functional effectors of endogenous HOXA9 and HOX-based leukemia oncoproteins, provide a concise in vivo platform to test RNA therapeutics, and suggest therapeutic value for microRNA antagonists in AML.

Related: Cytarabine Doxorubicin Acute Myeloid Leukemia (AML) miR-21 HOXA9 gene

Purizaca J, Contreras-Quiroz A, Dorantes-Acosta E, et al.
Lymphoid progenitor cells from childhood acute lymphoblastic leukemia are functionally deficient and express high levels of the transcriptional repressor Gfi-1.
Clin Dev Immunol. 2013; 2013:349067 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Acute lymphoblastic leukemia (ALL) is the most frequent malignancy of childhood. Substantial progress on understanding the cell hierarchy within ALL bone marrow (BM) has been recorded in the last few years, suggesting that both primitive cell fractions and committed lymphoid blasts with immature stem cell-like properties contain leukemia-initiating cells. Nevertheless, the biology of the early progenitors that initiate the lymphoid program remains elusive. The aim of the present study was to investigate the ability of lymphoid progenitors from B-cell precursor ALL BM to proliferate and undergo multilineage differentiation. By phenotype analyses, in vitro proliferation assays, and controlled culture systems, the lymphoid differentiation potentials were evaluated in BM primitive populations from B-cell precursor ALL pediatric patients. When compared to their normal counterparts, functional stem and progenitor cell contents were substantially reduced in ALL BM. Moreover, neither B nor NK or dendritic lymphoid-cell populations developed recurrently from highly purified ALL-lymphoid progenitors, and their proliferation and cell cycle status revealed limited proliferative capacity. Interestingly, a number of quiescence-associated transcription factors were elevated, including the transcriptional repressor Gfi-1, which was highly expressed in primitive CD34⁺ cells. Together, our findings reveal major functional defects in the primitive hematopoietic component of ALL BM. A possible contribution of high levels of Gfi-1 expression in the regulation of the stem/progenitor cell biology is suggested.

Related: Apoptosis Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Lee MC, Kuo YY, Chou WC, et al.
Gfi-1 is the transcriptional repressor of SOCS1 in acute myeloid leukemia cells.
J Leukoc Biol. 2014; 95(1):105-15 [PubMed] Related Publications
Silencing of SOCS1, a TSG, has been detected in various malignancies, including AML. However, the underlying mechanism of SOCS1 inactivation remains elusive. In this study, we explored the role of histone methylation in SOCS1 expression in AML cells. By ChIP assay, we demonstrated that G9a and SUV39H1, two enzymes catalyzing H3K9 methylation, were physically associated with the SOCS1 promoter, and treatment with chaetocin, a histone methyltransferase inhibitor, suppressed H3K9 methylation on the SOCS1 promoter and enhanced SOCS1 expression. Furthermore, knockdown of G9a and SUV39H1 by siRNA could also induce SOCS1 expression. On the other hand, SOCS1 knockdown by shRNA eliminated chaetocin-induced cell apoptosis. To investigate further whether any transcription factor was involved in H3K9 methylation-related SOCS1 repression, we scanned the sequences of the SOCS1 gene promoter and found two binding sites for Gfi-1, a transcription repressor. By DNA pull-down and ChIP assays, we showed that Gfi-1 directly bound the SOCS1 promoter, and ectopic Gfi-1 expression suppressed STAT5-induced SOCS1 promoter activation. In contrast, Gfi-1 knockdown by shRNA enhanced SOCS1 expression and inhibited STAT5 expression. Moreover, the knockdown of G9a completely rescued the repressive effect of Gfi-1 on STAT5A-induced SOCS1 promoter activation. Collectively, our study indicates that the expression of Gfi-1 contributes to SOCS1 silencing in AML cells through epigenetic modification, and suppression of histone methyltransferase can provide new insight in AML therapy.

Related: Apoptosis Acute Myeloid Leukemia (AML)

Khandanpour C, Möröy T
Growth factor independence 1 (Gfi1) as a regulator of p53 activity and a new therapeutical target for ALL.
Oncotarget. 2013; 4(3):374-5 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
The transcriptional repressor Gfi1 can be a so-called "oncorequisite" factor that is required for the development and maintenance of lymphoid neoplasia, such as Acute Lymphoblastic Leukemia (ALL), but does not have a direct role in the ontogeny of the disease. The study supporting this role of Gfi1 (Khandanpour C, Phelan J, et al., Cancer Cell, 2013, 23:200-214) shows that inhibition of Gfi1 cannot only cure mice from ALL but also blocks the expansion of human primary ALL cells. The study concludes that this feature of Gfi1 can be exploited to improve current ALL therapies.

Related: Apoptosis TP53

Huang H, Xiang Y, Su B, et al.
Potential roles for Gfi1 in the pathogenesis and proliferation of glioma.
Med Hypotheses. 2013; 80(5):629-32 [PubMed] Related Publications
Glioblastoma multiforme (GBM) is a major form of adult brain tumour with relatively poor prognosis and high mortality. Temozolomide (TMZ)-based chemotherapy following neurosurgery and radiotherapy has been suggested as the first line of treatment and is proven to effectively prolong overall survival and enhance patient quality of life. However, not all patients benefit from this treatment because of drug resistance. Even patients with TMZ-sensitive GBM may become resistant, which is partly due to the restoration of activity of the DNA repair enzyme O(6)-methylguanine-DNA-methyltransferase (MGMT); thus, patients cannot evade eventual tumour recurrence. The cellular activity of MGMT is the most important determinant of TMZ-resistance. However, some patients with a low level of activated MGMT are also TMZ-resistant. The aberrant expression of HOXA9, one of the 39 class I homeobox genes, is a marker of poor prognosis, and its level gradually increases with histologic malignant progression, shorter time to overall survival (OS) and free progression survival (FPS) in glioma patients, which further supports an oncogenic role for HOXA9 in gliomas. The HOXA9-PI3K signalling pathway is an important mechanism in GBM that is independent of MGMT promoter methylation status. The DNA binding sites of growth factor independent-1 (Gfi1) can overlap with the HOXA9 promoter through the "AATC" versus "GATT" core sequence. The competition for this binding site inhibits the expression of HOXA9 and induces different transcriptional outcomes, which suggests a new direction for investigation of the mechanism underlying targeted therapy of malignant gliomas.

Related: HOXA9 gene

Sandoval S, Kraus C, Cho EC, et al.
Sox4 cooperates with CREB in myeloid transformation.
Blood. 2012; 120(1):155-65 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
The cAMP response element-binding protein (CREB) is a nuclear transcription factor that is critical for normal and neoplastic hematopoiesis. Previous studies have demonstrated that CREB is a proto-oncogene whose overexpression promotes cellular proliferation in hematopoietic cells. Transgenic mice that overexpress CREB in myeloid cells develop a myeloproliferative disease with splenomegaly and aberrant myelopoiesis. However, CREB overexpressing mice do not spontaneously develop acute myeloid leukemia. In this study, we used retroviral insertional mutagenesis to identify genes that accelerate leukemia in CREB transgenic mice. Our mutagenesis screen identified several integration sites, including oncogenes Gfi1, Myb, and Ras. The Sox4 transcription factor was identified by our screen as a gene that cooperates with CREB in myeloid leukemogenesis. We show that the transduction of CREB transgenic mouse bone marrow cells with a Sox4 retrovirus increases survival and self-renewal of cells in vitro. Furthermore, leukemic blasts from the majority of acute myeloid leukemia patients have higher CREB, phosphorylated CREB, and Sox 4 protein expression. Sox4 transduction of mouse bone marrow cells results in increased expression of CREB target genes. We also demonstrate that CREB is a direct target of Sox4 by chromatin immunoprecipitation assays. These results indicate that Sox4 and CREB cooperate and contribute to increased proliferation of hematopoietic progenitor cells.

Related: Acute Myeloid Leukemia (AML) CREB1 gene

Tuupanen S, Yan J, Turunen M, et al.
Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583.
Cancer Genet. 2012 Jan-Feb; 205(1-2):25-33 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Recent genome-wide association studies have identified multiple regions at 8q24 that confer susceptibility to many cancers. In our previous work, we showed that the colorectal cancer (CRC) risk variant rs6983267 at 8q24 resides within a TCF4 binding site at the MYC-335 enhancer, with the risk allele G having a stronger binding capacity and Wnt responsiveness. Here, we searched for other potential functional variants within MYC-335. Genetic variation within MYC-335 was determined in samples from individuals of European, African, and Asian descent, with emphasis on variants in putative transcription factor binding sites. A 2-bp GA deletion rs67491583 was found to affect a growth factor independent (GFI) binding site and was present only in individuals with African ancestry. Chromatin immunoprecipitation performed in heterozygous cells showed that the GA deletion had an ability to reduce binding of the transcriptional repressors GFI1 and GFI1b. Screening of 1,027 African American colorectal cancer cases and 1,773 healthy controls did not reveal evidence for association (odds ratio: 1.17, 95% confidence interval: 0.97-1.41, P = 0.095). In this study, rs67491583 was identified as another functional variant in the CRC-associated enhancer MYC-335, but further studies are needed to establish the role of rs67491583 in the colorectal cancer predisposition of African Americans.

Related: Chromosome 8 Colorectal (Bowel) Cancer

Soliera AR, Mariani SA, Audia A, et al.
Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1.
Leukemia. 2012; 26(7):1555-63 [PubMed] Related Publications
Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

D'Souza S, del Prete D, Jin S, et al.
Gfi1 expressed in bone marrow stromal cells is a novel osteoblast suppressor in patients with multiple myeloma bone disease.
Blood. 2011; 118(26):6871-80 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Protracted inhibition of osteoblast (OB) differentiation characterizes multiple myeloma (MM) bone disease and persists even when patients are in long-term remission. However, the underlying pathophysiology for this prolonged OB suppression is unknown. Therefore, we developed a mouse MM model in which the bone marrow stromal cells (BMSCs) remained unresponsive to OB differentiation signals after removal of MM cells. We found that BMSCs from both MM-bearing mice and MM patients had increased levels of the transcriptional repressor Gfi1 compared with controls and that Gfi1 was a novel transcriptional repressor of the critical OB transcription factor Runx2. Trichostatin-A blocked the effects of Gfi1, suggesting that it induces epigenetic changes in the Runx2 promoter. MM-BMSC cell-cell contact was not required for MM cells to increase Gfi1 and repress Runx2 levels in MC-4 before OBs or naive primary BMSCs, and Gfi1 induction was blocked by anti-TNF-α and anti-IL-7 antibodies. Importantly, BMSCs isolated from Gfi1(-/-) mice were significantly resistant to MM-induced OB suppression. Strikingly, siRNA knockdown of Gfi1 in BMSCs from MM patients significantly restored expression of Runx2 and OB differentiation markers. Thus, Gfi1 may have an important role in prolonged MM-induced OB suppression and provide a new therapeutic target for MM bone disease.

Related: Bone Cancers Myeloma Myeloma - Molecular Biology TNF

Lee KM, Choi WI, Koh DI, et al.
The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding.
Oncogene. 2012; 31(11):1442-58 [PubMed] Related Publications
The BTB/POZ family of proteins has been implicated in multiple biological processes, including tumourigenesis, DNA damage responses and cell cycle progression and development. MIZ-1 (Myc-interacting zinc-finger protein 1) is known to activate transcription of CDKN1A. We recently found that a kidney cancer-related POK transcription factor, KR-POK, is highly expressed in kidney, brain and bone marrow cancer tissues and is a potential proto-oncoprotein. Mouse Kr-pok represses transcription of the CDKN1A by acting on the proximal promoter. The BiFC/FRET assay, co-immunoprecipitation and glutathione S-transferase-fusion protein pull-down assay indicate that MIZ-1 and Kr-pok interact via their POZ domains. Oligoucleotide pull-down assays and chromatin immunoprecipitation assays revealed that MIZ-1 binds to the proximal GC-box#3 (bp, -55 to -63) and the MIZ-1-binding elements, MRE-A (bp, -90 to -64) and MRE-B (bp, -27 to -17). Interestingly, MIZ-1 also binds to the distal p53-binding elements. Kr-pok binds to the proximal GC-box#1 (bp, -95 to -100) and #3 (bp, -55 to -63) relatively strongly. It also shows weak binding to the MREs and the distal p53-binding elements. Kr-pok competes with MIZ-1 in binding to these elements and represses transcription by inhibiting MIZ-1/p300 recruitment, which decreases the acetylation of histones H3 and H4. Our data indicate that Kr-pok stimulates cell proliferation by interfering with the function of MIZ-1 in CDKN1A gene transcription using a mechanism that is radically different from other MIZ-1-interacting proteins, such as B-cell lymphoma 6, c-Myc and Gfi-1.

Related: CDKN1A

Bonadies N, Foster SD, Chan WI, et al.
Genome-wide analysis of transcriptional reprogramming in mouse models of acute myeloid leukaemia.
PLoS One. 2011; 6(1):e16330 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.

Related: GATA2 gene Acute Myeloid Leukemia (AML)

Phelan JD, Shroyer NF, Cook T, et al.
Gfi1-cells and circuits: unraveling transcriptional networks of development and disease.
Curr Opin Hematol. 2010; 17(4):300-7 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
PURPOSE OF REVIEW: The review will integrate current knowledge of transcriptional circuits whose dysregulation leads to autoimmunity, neutropenia and leukemia.
RECENT FINDINGS: Growth factor independent-1 (Gfi1) is a transcriptional repressor with essential roles in controlling hematopoietic stem cell biology, myeloid and lymphoid differentiation and lymphocyte effector functions. Recent work has suggested that Gfi1 competes or collaborates with other transcription factors to modulate transcription programs and lineage decisions.
SUMMARY: Gfi1 is central to several transcriptional circuits whose dysregulation leads to abnormal or malignant hematopoiesis. These functional relationships are conserved from Drosophila development. Such conserved pathways represent central oncogenic or 'gatekeeper' pathways that are pivotal to understanding the process of cellular transformation, and illustrate key targets for clinical intervention.

Related: Leukemia Signal Transduction

Liu Q, Basu S, Qiu Y, et al.
A role of Miz-1 in Gfi-1-mediated transcriptional repression of CDKN1A.
Oncogene. 2010; 29(19):2843-52 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
Zinc-finger (ZF) transcriptional repressor growth factor independence 1 (Gfi-1) has an important role in hematopoiesis and inner ear development, and also functions as an oncoprotein that cooperates with c-Myc in lymphomagenesis. Gfi-1 represses transcription by directly binding to conserved sequences in the promoters of its target genes. CDKN1A encoding p21(Cip1) has been identified as a Gfi-1 target gene and has been shown to contain Gfi-1 binding sites in the upstream promoter region. We show here that Gfi-1 represses CDKN1A in a manner that is independent of its DNA binding activity. Gfi-1 interacts with POZ-ZF transcription factor Miz-1, originally shown to be a c-Myc-interacting partner, and through Miz-1 binds to the CDKN1A core promoter. Interestingly, Gfi-1 and c-Myc, through Miz-1, form a ternary complex on the CDKN1A promoter, and function in collaboration to repress CDKN1A. Gfi-1 knockdown results in enhanced levels of p21(Cip1) and attenuated cell proliferation. Notably, similar to c-Myc, the expression of Gfi-1 is downregulated by transforming growth factor-beta (TGFbeta) and the level of Gfi-1 influences the response of cells to the cytostatic effect of TGFbeta. Our data reveal an important mechanism by which Gfi-1 regulates cell proliferation and may also have implications for understanding the role of Gfi-1 in lymphomagenesis.

Related: CDKN1A

Khandanpour C, Thiede C, Valk PJ, et al.
A variant allele of Growth Factor Independence 1 (GFI1) is associated with acute myeloid leukemia.
Blood. 2010; 115(12):2462-72 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
The GFI1 gene encodes a transcriptional repressor, which regulates myeloid differentiation. In the mouse, Gfi1 deficiency causes neutropenia and an accumulation of granulomonocytic precursor cells that is reminiscent of a myelodysplastic syndrome. We report here that a variant allele of GFI1 (GFI1(36N)) is associated with acute myeloid leukemia (AML) in white subjects with an odds ratio of 1.6 (P < 8 x 10(-5)). The GFI1(36N) variant occurred in 1806 AML patients with an allele frequency of 0.055 compared with 0.035 in 1691 healthy control patients in 2 independent cohorts. We observed that both GFI1 variants maintain the same activity as transcriptional repressors but differ in their regulation by the AML1/ETO (RUNX1/RUNX1T1) fusion protein produced in AML patients with a t(8;21) translocation. AML1/ETO interacts and colocalizes with the more common GFI1(36S) form in the nucleus and inhibits its repressor activity. However, the variant GFI1(36N) protein has a different subnuclear localization than GFI1(36S). As a consequence, AML1/ETO does not colocalize with GFI1(36N) and is unable to inhibit its repressor activity. We conclude that both variants of GFI1 differ in their ability to be regulated by interacting proteins and that the GFI1(36N) variant form exhibits distinct biochemical features that may confer a predisposition to AML.

Related: Acute Myeloid Leukemia (AML)

Yamasaki N, Miyazaki K, Nagamachi A, et al.
Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia.
Oncogene. 2010; 29(13):1963-75 [PubMed] Related Publications
E2A-hepatic leukemia factor (HLF) is a chimeric protein found in B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: growth factor independent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be overexpressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)-positive B-lineage ALL.

Related: Acute Lymphocytic Leukemia (ALL) ZNF521 gene

Katoh M, Katoh M
Integrative genomic analyses of CXCR4: transcriptional regulation of CXCR4 based on TGFbeta, Nodal, Activin signaling and POU5F1, FOXA2, FOXC2, FOXH1, SOX17, and GFI1 transcription factors.
Int J Oncol. 2010; 36(2):415-20 [PubMed] Related Publications
CXCR4, CD133, CD44 and ABCG2 are representative transmembrane proteins expressed on the surfaces of normal and/or cancer stem cells. CXCR4 is co-expressed with POU5F1 in endodermal precursors and adult-tissue stem cells. CXCR4 is expressed in a variety of human tumors, such as breast cancer, prostate cancer, pancreatic cancer, and gastric cancer. CXCR4 is a G protein-coupled receptor (GPCR) for CXCL12 (SDF1) chemokine, and the CXCL12-CXCR4 signaling axis is involved in proliferation, survival, migration, and homing of cancer cells. Integrative genomic analyses of CXCR4 gene were carried out to elucidate the mechanisms of CXCR4 expression in stem cells, because CXCR4 is a key molecule occupying the crossroads of oncology, immunology, gerontology and regenerative medicine. Human CXCR4 promoter region with binding sites for HIF1alpha, ETS1, NF-kappaB and GLI was not conserved in mouse and rat Cxcr4 orthologs. Proximal enhancer region with palindromic Smad-binding sites, FOX-binding site, POU-binding site, triple SOX17-binding sites, bHLH-binding site, TCF/LEF-binding site, and double GFI1-binding sites was almost completely conserved among human, chimpanzee, mouse, and rat CXCR4 orthologs. TGFbeta, Nodal, and Activin signals induce CXCR4 upregulation based on Smad2/3 and FOX family members, such as FOXA2, FOXC2, and FOXH1. CXCR4 is expressed in endodermal precursors due to the existence of triple SOX17-binding sites around the POU-binding site instead of the POU5F1-SOX2 joint motif. Because CXCR4 is downregulated by p53-GFI1 signaling axis, p53 mutation in cancer stem cells leads to CXCR4 upregulation. CXCR4 is also upregulated by TGFbeta and Hedgehog signals in tumor cells at the invasion front. Small molecule compound or human antibody targeted to CXCR4 will be applied for cancer therapeutics focusing on cancer stem cells at the primary lesion as well as metastasis or recurrence niches, such as bone marrow and peritoneal cavity.

Related: CGH Cancer Prevention and Risk Reduction Signal Transduction

Huang M, Hu Z, Chang W, et al.
The growth factor independence-1 (Gfi1) is overexpressed in chronic myelogenous leukemia.
Acta Haematol. 2010; 123(1):1-5 [PubMed] Related Publications
The activation of ABL tyrosine kinase in BCR/ABL-positive chronic myelogenous leukemia (CML) leads to a diversity of biological changes related to the pathogenesis of the disease. In CML patients, we determined the expression of growth factor independence-1 (Gfi1), a transcription repressor with weak oncogenic activity. Our data demonstrated that the Gfi1 mRNA level in both the mononuclear cells and purified CD34(+) cells from CML were significantly higher as measured by quantitative real-time PCR. Using flow cytometry and Western blot, we also showed that the Gfi1 protein content was increased in CML CD34(+) cells. The expression of Gfi1 was correlated with BCR/ABL significantly. Gfi1 may be implicated in the pathogenesis of CML and can serve as a potential target for the management of the disease.

Related: ABL1 Chronic Myeloid Leukemia (CML) CML - Molecular Biology Stem Cell and Bone Marrow Transplants Imatinib (Glivec)

Noah TK, Kazanjian A, Whitsett J, Shroyer NF
SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells.
Exp Cell Res. 2010; 316(3):452-65 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
BACKGROUND AND AIMS: SPDEF (also termed PDEF or PSE) is an ETS family transcription factor that regulates gene expression in the prostate and goblet cell hyperplasia in the lung. Spdef has been reported to be expressed in the intestine. In this paper, we identify an important role for Spdef in regulating intestinal epithelial cell homeostasis and differentiation.
METHODS: SPDEF expression was inhibited in colon cancer cells to determine its ability to control goblet cell gene activation. The effects of transgenic expression of Spdef on intestinal differentiation and homeostasis were determined.
RESULTS: In LS174T colon cancer cells treated with Notch/gamma-secretase inhibitor to activate goblet cell gene expression, shRNAs that inhibited SPDEF also repressed expression of goblet cell genes AGR2, MUC2, RETLNB, and SPINK4. Transgenic expression of Spdef caused the expansion of intestinal goblet cells and corresponding reduction in Paneth, enteroendocrine, and absorptive enterocytes. Spdef inhibited proliferation of intestinal crypt cells without induction of apoptosis. Prolonged expression of the Spdef transgene caused a progressive reduction in the number of crypts that expressed Spdef, consistent with its inhibitory effects on cell proliferation.
CONCLUSIONS: Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells; SPDEF was required for activation of goblet cell associated genes in vitro. These data support a model in which Spdef promotes terminal differentiation into goblet cells of a common goblet/Paneth progenitor.

Vassen L, Khandanpour C, Ebeling P, et al.
Growth factor independent 1b (Gfi1b) and a new splice variant of Gfi1b are highly expressed in patients with acute and chronic leukemia.
Int J Hematol. 2009; 89(4):422-30 [PubMed] Related Publications
Gfi1b is a transcriptional repressor that is essential for erythroid cells and megakaryocytes, but is also expressed in hematopoietic stem cells and early myeloid progenitors. The chromosomal localization of the Gfi1b gene at 9q34 and its functional homology with the proto-oncogene Gfi1 were suggestive for a role of Gfi1b in malignant transformation and myeloid leukemia. We show here that the expression of Gfi1b is strongly elevated in CML and AML patients compared to normal healthy controls and that imatinib, a drug widely used to treat CML, further enhances Gfi1b expression in patients even after remission. Our data suggest that Gfi1b may be an important factor to establish or maintain myeloid leukemia and myeloproliferative diseases and that, high expression levels of Gfi1b might be associated with the emergence of Philadelphia chromosome negative myeloid malignancies after imatinib withdrawal or after the development of imatinib resistance.

Related: Leukemia GLI Imatinib (Glivec)

Ossovskaya VS, Dolganov G, Basbaum AI
Loss of function genetic screens reveal MTGR1 as an intracellular repressor of beta1 integrin-dependent neurite outgrowth.
J Neurosci Methods. 2009; 177(2):322-33 [PubMed] Related Publications
Integrins are transmembrane receptors that promote neurite growth and guidance. To identify regulators of integrin-dependent neurite outgrowth, here we used two loss of function genetic screens in SH-SY5Y neuroblastoma cells. First, we screened a genome-wide retroviral library of genetic suppressor elements (GSEs). Among the many genes identified in the GSE screen, we isolated the hematopoetic transcriptional factor MTGR1 (myeloid translocation gene-related protein-1). Treatment of SH-SY5Y cells with MTGR1 siRNA enhanced neurite outgrowth and concurrently increased expression of GAP-43, a protein linked to neurite outgrowth. Second, we transduced SH-SY5Y with a genome-wide GFP-labeled lentiviral siRNA library, which expressed 40,000 independent siRNAs targeting 8500 human genes. From this screen we isolated GFI1 (growth factor independence-1), which, like MTGR1, is a member of the myeloid translocation gene on 8q22 (MTG8)/ETO protein complex of nuclear repressor proteins. These results reveal novel contributions of MTGR1 and GFI1 to the regulation of neurite outgrowth and identify novel repressors of integrin-dependent neurite outgrowth.

Related: ITGB1 Neuroblastoma

Yamada H, Sekikawa T, Iwase S, et al.
Segregation of megakaryocytic or erythroid cells from a megakaryocytic leukemia cell line (JAS-R) by adhesion during culture.
Leuk Res. 2007; 31(11):1537-43 [PubMed] Related Publications
Adhesion is one of the important biologic characteristics of leukemic cells. We previously reported a new megakaryocytic-erythroid cell line, JAS-R. In this study, JAS-R cells were segregated into two types by the differences of attachment to culture dishes. One type (designated as JAS-RAD cells) adhered to the substratum of the culture dishes, while the other (JAS-REN cells) grew as a single-cell suspension. Adhesion of JAS-RAD was inhibited by treatment with RGDS oligopeptide. Flow cytometric analysis revealed that JAS-RAD cells had high expression of CD41a and CD61 versus low CD235a expression, and JAS-REN showed low expression of CD41a, and CD61, and high CD235a. The two phenotypes were reciprocally exchangeable by selecting adherent or suspended cells from each type of culture. Microarray analysis and RT-PCR revealed that JAS-RAD cells expressed four major alpha-granule genes and JAS-REN cells expressed beta-globin. Interestingly, erythropoietin was only secreted by JAS-RAD cells. With regard to transcription factors, it was shown that GFI1, FLI1 and RUNX1 were strongly expressed in JAS-RAD cells while GATA1, FOG1 and NFE2 were equally expressed by both types. These findings indicate that adhesion via integrins is related to the phenotypic shift of JAS-R cells between megakaryocytic and erythroid lineages.

Dwivedi PP, Anderson PH, Tilley WD, et al.
Role of oncoprotein growth factor independent-1 (GFI1) in repression of 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1): a comparative analysis in human prostate cancer and kidney cells.
J Steroid Biochem Mol Biol. 2007; 103(3-5):742-6 [PubMed] Related Publications
1,25-Dihydroxyvitamin D (1,25D) inhibits growth of prostate cancer cells and has been proposed to play a protective role in prostate cancer. However, 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1), the enzyme responsible for the cellular synthesis of 1,25D, is repressed in prostate cancer cells. Recently, we have identified a role for the transcription factor, Growth Factor Independent-1 (GFI1) in the repression of the CYP27B1 gene in human prostate cancer cell lines. GFI1 is known to form a large protein complex with co-repressors that recruit histone deacetylases. We have proposed a model for the molecular repression of CYP27B1 gene expression. The formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to the silencing of gene expression either by inactivating nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies demonstrate that GFI1 may play a significant role in the down regulation of endogenous production of 1,25D in prostate cancer cells and could provide a novel insight to future diagnosis and treatment.

Related: Prostate Cancer

Hochberg JC, Miron PM, Hay BN, et al.
Mosaic tetraploidy and transient GFI1 mutation in a patient with severe chronic neutropenia.
Pediatr Blood Cancer. 2008; 50(3):630-2 [PubMed] Related Publications
This report presents the case of a 15-year-old male with severe chronic neutropenia, leukopenia, and persistent tetraploid mosaicism in the bone marrow and peripheral blood. His father had mild neutropenia and bone marrow tetraploidy. Flow cytometric analysis of DNA content peripheral blood showed tetraploidy in 20% of granulocytes and 15% of monocytes. Sequence analysis of the ELA2 gene was normal, but the GFI1 gene exhibited transient appearance of single base changes the coding region and promoter. We speculate that an underlying genetic defect, inherited in an autosomal dominant pattern, leads to both disordered mitosis and neutropenia in this kindred.

Related: Leukemia

Kumar R, Manning J, Spendlove HE, et al.
ZNF652, a novel zinc finger protein, interacts with the putative breast tumor suppressor CBFA2T3 to repress transcription.
Mol Cancer Res. 2006; 4(9):655-65 [PubMed] Related Publications
The transcriptional repressor CBFA2T3 is a putative breast tumor suppressor. To define the role of CBFA2T3, we used a segment of this protein as bait in a yeast two-hybrid screen and identified a novel uncharacterized protein, ZNF652. In general, primary tumors and cancer cell lines showed lower expression of ZNF652 than normal tissues. Together with the location of this gene on the long arm of chromosome 17q, a region of frequent loss of heterozygosity in cancer, these results suggest a possible role of ZNF652 in tumorigenesis. In silico analysis of this protein revealed that it contains multiple classic zinc finger domains that are predicted to bind DNA. Coimmunoprecipitation assays showed that ZNF652 strongly interacts with CBFA2T3 and this interaction occurs through the COOH-terminal 109 amino acids of ZNF652. In contrast, there was a weak interaction of ZNF652 with CBFA2T1 and CBFA2T2, the other two members of this ETO family. Transcriptional reporter assays further confirmed the strength and selectivity of the ZNF652-CBFA2T3 interaction. The transcriptional repression of growth factor independent-1 (GFI-1), a previously characterized ETO effector zinc finger protein, was shown to be enhanced by CBFA2T1, but to a lesser extent by CBFA2T2 and CBFA2T3. We therefore suggest that each of the various gene effector zinc finger proteins may specifically interact with one or more of the ETO proteins to generate a defined range of transcriptional repressor complexes.

Related: Breast Cancer

Schwartz R, Engel I, Fallahi-Sichani M, et al.
Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development.
Proc Natl Acad Sci U S A. 2006; 103(26):9976-81 [PubMed] Article available free on PMC after 24/07/2015 Related Publications
In maturing T lineage cells, the helix-loop-helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred to as beta selection. To examine how E47 regulates cellular expansion and developmental progression, we have used an E2A-deficient lymphoma cell line and DNA microarray analysis to identify immediate E47 target genes. Hierarchical cluster analysis of gene expression patterns revealed that E47 coordinately regulates the expression of genes involved in cell survival, cell cycle progression, lipid metabolism, stress response, and lymphoid maturation. These include Plcgamma2, Cdk6, CD25, Tox, Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2, and Xbp1. We propose a regulatory network linking Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated signaling, E47, and suppressor of cytokine signaling (SOCS) proteins in a common pathway. Finally, we suggest that the aberrant activation of Cdk6 in E47-deficient T lineage cells contributes to the development of lymphoid malignancy.

Related: Cytokines Signal Transduction

Carlsson G, Aprikyan AA, Ericson KG, et al.
Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.
Haematologica. 2006; 91(5):589-95 [PubMed] Related Publications
BACKGROUND AND OBJECTIVES: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN.
DESIGN AND METHODS: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes.
RESULTS: One patient belonging to the original Kostmann family harbored a novel heterozygous ELA-2 mutation (g.2310T-->A;Leu92His) that was not inherited from her parents. The mutation was identified in DNA isolated from both whole blood and skin fibroblasts, suggesting a sporadic de novo mutation. As a young adult this patient sequentially acquired two mutations in the gene for the G-CSF receptor (G-CSFR) and therefore recently received a hematopoietic stem cell transplant, due to the risk of evolution to leukemia. Moreover, another patient developed acute leukemia and was treated with transplantation. No pathogenic ELA-2 or G-CSFR gene mutations were found in this patient or the other two patients, nor in any healthy relative.
INTERPRETATION AND CONCLUSIONS: Our data are the first to document leukemia evolution and G-CSFR gene mutations in the original Kostmann kindred. In addition, our findings indicate that ELA-2 mutations are not the primary cause of SCN in the Swedish Kostmann family.

Dwivedi PP, Anderson PH, Omdahl JL, et al.
Identification of growth factor independent-1 (GFI1) as a repressor of 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) gene expression in human prostate cancer cells.
Endocr Relat Cancer. 2005; 12(2):351-65 [PubMed] Related Publications
The hormone 1,25-dihydroxyvitamin D (1,25D) may play a protective role in prostate cancer. 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) is the enzyme responsible for the regulation of cellular 1,25D levels. CYP27B1 is substantially repressed in prostate cancer cells. We have investigated the molecular basis for this inhibition. First, we identify a repressive region between -997 and -1200 in the human CYP27B1 promoter following transient transfection analysis in the prostate cancer cell lines DU145, PC3 and LNCaP. Next, we demonstrate a role for the transcription factor growth factor independent-1 (GFI1) in the repression of CYP27B1. Electrophoretic mobility assays with nuclear extracts from prostate cancer cell lines established binding of GFI1 to the sequence 5'-TGGTACAATCATAACTCACTGCAG-3' present at -997 to -1200 in the repressive region. Site directed mutagenesis of the core GFI1 binding sequence (5'-AATC-3') substantially increased while forced expression of GFI1 decreased the expression of the CYP27B1 reporter construct. Importantly, GFI1 repression is dependent on an intact GFI1 binding site in the -997 to -1200 region. GFI1 is an oncoprotein known to form a large protein complex with co-repressors that recruit histone deacetylases. We propose that the formation of such a repressive complex on the inhibitory domain of the CYP27B1 gene in prostate cancer cells could lead to silencing of either the nearby enhancer or proximal promoter domains and lead to cancer progression by reducing local production of 1,25D. These studies provide the basis for a more detailed understanding of CYP27B1 repression in prostate cancer cells and could provide a novel insight in future diagnosis and treatment.

Related: Prostate Cancer


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