Article

Elmaagacli AH, Koldehoff M, Zakrzewski JL, Steckel NK, Ottinger H, Beelen DW.. Growth factor-independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate. Br J Haematol 136: 212-219

Department of Bone Marrow Transplantation, University Hospital of Essen, Essen, Germany.
British Journal of Haematology (Impact Factor: 4.71). 01/2007; 136(2):212-9. DOI: 10.1111/j.1365-2141.2006.06407.x
Source: PubMed

ABSTRACT

Growth factor-independent 1B (GFI1B) is a transcription factor essential for the development and differentiation of erythroid and megakaryocytic lineages. We evaluated the GFI1B expression in erythroleukaemia and megakaryocytic leukaemia, as well as in patients with other subtypes of acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), myelodysplastic syndrome (MDS), severe aplastic anaemia (SAA), myelofibrosis with myeloid metaplasia (MMM) and in healthy volunteers. GFI1B expression was increased at least threefold in patients with erythroleukaemia (P < 0.01 compared with controls) and megakaryocytic leukaemia (P < 0.05) as well as in their corresponding leukaemic cell lines HEL, K562, CMK and M-07e. Patients with undifferentiated or monocytic AML, ALL, MMM, MDS and CML had no significantly altered GFI1B expression, whereas GFI1B expression was decreased 10-fold in patients with SAA (P < 0.0001 compared with controls). Silencing GFI1B by transfection with small interfering RNA (siRNA) markedly reduced the proliferation rate in the leukaemic cell lines HEL, K562 and NB4 (P < 0.01). Concomitantly, we observed a two- to threefold increase in the apoptosis rate in these cells after transfection with siRNA towards GFI1B. Our data indicate that GFI1B plays a major role in AML-M6 and AML-M7 and qualifies as a target for anti-leukaemic strategies in these malignancies.

  • Source
    • "In 1933, Gilks first identified the GFI1 gene in the integration sites of rat T cell lymphoma, which is located in chromosome 1p22 of the human genome (Gilks et al., 1993, Rödel et al., 1998). In 1998, Rödel (Elmaagacli et al., 2007) found that the GFI1B gene was located in chromosome 9q34.13 of the human genome. Several studies have shown that GRI1B is a nuclear transcriptional repressor encoding 329 amino acids, which contains an N-terminal SNAG domain composed of 20 amino acids, and a C2H2-like zinc finger domain containing six carboxyl ends. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to investigate polymorphisms of the eighth exon in the GFI1B gene among three indigenous Chinese goat breeds (QianBei Ma goats, GuiZhou white goats, and GuiZhou black goats). Furthermore, association analysis was conducted between these polymorphisms and growth traits. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct DNA sequencing, and PCR-restricted fragment length polymorphism (RFLP) were applied to detect polymorphism sites, and a general linear model was used to analyze their association with growth traits. We found two consistent single nucleotide polymorphism (SNP) sites in the eighth exon of the GFI1B gene among the three breeds: 263 bp G→T and 340 bp G→A. The fixed effects model used to analyze growth traits revealed significant differences in body weight, body length, chest depth, and chest breadth between genotypes CD, CC, and DD (P < 0.01). The 340(G/C) polymorphic sites identified here will provide a basis to further study associations between the GFI1B gene and growth traits, as well as establish a theoretical foundation to develop better feeding and genetic resources of indigenous goats.
    Preview · Article · Mar 2014 · Genetics and molecular research: GMR
  • Source
    • "Growth factor independence-1B (GFI-1B) is a transcription factor that controls the development and differentiation of erythroid cells and megakaryocytes at the erythro-megakaryocytic progenitor stage (Randrianarison-Huetz et al. 2010). GPI1B mRNA expression was found to be overexpressed in leukemic cells (Elmaagacli et al. 2007). Koldehoff et al. investigated whether antileukemic effect of BCR-ABL silencing can be further increased by co-silencing of GFI1B (Koldehoff et al. 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Leukemic cancers arise from genetic alterations in normal hematopoietic stem or progenitor cells, leading to impaired regulation of proliferation, differentiation, apoptosis and survival of the malignant cells. A range of molecular alterations is beginning to be elucidated in specific types of leukemias, providing potential targets for molecular modulation as the basis of a therapy. With the advent of RNA interference (RNAi) and, in particular, the short interfering RNA (siRNA) as its pharmacological mediator, it is becoming possible to specifically modulate desired leukemic targets at will. This chapter will summarize the current attempts to utilize siRNAs in leukemic therapy using chronic myeloid leukemia (CML) as a prototypical disease model. We first provide a brief background on the CML disease with particular emphasis on molecular mediators critical in this disease and the current drug therapy. The limitations of current drugs and potential of RNAi are presented. We then provide a summary of delivery efforts employed to deliver siRNA to CML cells, with emphasis on non-viral delivery approach due to its better safety profile for utility in a clinical setting. Important factors involved in intracellular delivery of siRNA are highlighted, emphasizing features critical for non-viral delivery. We conclude with a perspective on the future of siRNA therapy for the CML disease.
    Full-text · Chapter · Jan 2014
  • Source
    • "Over-expression of Gfi1 and Gfi1b have been observed in induced and naturally occurring lymphoid and myeloid leukemias in mice and humans respectively [9], [13], [14], [15], [16], [17], [18], [19], [21]. However, the causal role of these genes if any in initiation or maintenance of these leukemias is not clear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Gfi1b (growth factor independence 1b) is a zinc finger transcription factor essential for development of the erythroid and megakaryocytic lineages. To elucidate the mechanism underlying Gfi1b function, potential downstream transcriptional targets were identified by chromatin immunoprecipitation and expression profiling approaches. The combination of these approaches revealed the oncogene meis1, which encodes a homeobox protein, as a direct and prominent target of Gfi1b. Examination of the meis1 promoter sequence revealed multiple Gfi1/1b consensus binding motifs. Distinct regions of the promoter were occupied by Gfi1b and its cofactors LSD1 and CoREST/Rcor1, in erythroid cells but not in the closely related megakaryocyte lineage. Accordingly, Meis1 was significantly upregulated in LSD1 inhibited erythroid cells, but not in megakaryocytes. This lineage specific upregulation in Meis1 expression was accompanied by a parallel increase in di-methyl histone3 lysine4 levels in the Meis1 promoter in LSD1 inhibited, erythroid cells. Meis1 was also substantially upregulated in gfi1b-/- fetal liver cells along with its transcriptional partners Pbx1 and several Hox messages. Elevated Meis1 message levels persisted in gfi1b mutant fetal liver cells differentiated along the erythroid lineage, relative to wild type. However, cells differentiated along the megakaryocytic lineage, exhibited no difference in Meis1 levels between controls and mutants. Transfection experiments further demonstrated specific repression of meis1 promoter driven reporters by wild type Gfi1b but neither by a SNAG domain mutant nor by a DNA binding deficient one, thus confirming direct functional regulation of this promoter by the Gfi1b transcriptional complex. Overall, our results demonstrate direct yet differential regulation of meis1 transcription by Gfi1b in distinct hematopoietic lineages thus revealing it to be a common, albeit lineage specific, target of both Gfi1b and its paralog Gfi1.
    Full-text · Article · Jan 2013 · PLoS ONE
Show more