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


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.

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    • "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. "
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    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.
    PLoS ONE 01/2013; 8(1):e53666. DOI:10.1371/journal.pone.0053666 · 3.23 Impact Factor
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    • "Gfi-1b is essential for terminal megakaryocyte maturation, as Gfi-1b-deficient fetal liver progenitors give rise to small, poorly formed megakaryocyte colonies comprised of cells that express significantly reduced levels of von- Willebrand factor, gpIIb, c-mpl and NF-E2 compared to wild-type cells (Saleque et al., 2002). Interestingly, GFI-1B appears to be overexpressed in both erythroid and megakaryocytic human malignancies where it may contribute to the increased proliferation of leukemic cells (Elmaagacli et al., 2007). Another transcriptional regulator that is essential for platelet biosynthesis is NF-E2, which promotes expression of mid-late stage megakaryocyte genes including b1-tubulin (Shivdasani et al., 1995; Chen et al., 2007). "
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    ABSTRACT: Red blood cells and megakaryocytes arise from a common precursor, the megakaryocyte-erythroid progenitor and share many regulators including the transcription factors GATA-1 and GFI-1B and signaling molecules such as JAK2 and STAT5. These lineages also share the distinction of being associated with rare, but aggressive malignancies that have very poor prognoses. In this review, we will briefly summarize features of normal development of red blood cells and megakaryocytes and also highlight events that lead to their leukemic transformation. It is clear that much more work needs to be done to improve our understanding of the unique biology of these leukemias and to pave the way for novel targeted therapeutics.
    Oncogene 11/2007; 26(47):6803-15. DOI:10.1038/sj.onc.1210763 · 8.46 Impact Factor
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    ABSTRACT: Gfi-1 and Gfi-1b are homologous transcriptional repressors involved in diverse developmental contexts, including hematopoiesis and oncogenesis. Transcriptional repression by Gfi proteins requires the conserved SNAG domain. To elucidate the function of Gfi proteins, we purified Gfi-1b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSD1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain. Gfi-1b further recruits these cofactors to the majority of target gene promoters in vivo. Inhibition of CoREST and LSD1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 methylation at the respective promoters. Overall, we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors through interaction with Gfi proteins controls hematopoietic differentiation.
    Molecular Cell 09/2007; 27(4):562-72. DOI:10.1016/j.molcel.2007.06.039 · 14.02 Impact Factor
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