Growth factor‐independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate

Abstract

SummaryGrowth 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 < 0AE01 compared with controls) and megakaryocytic leukaemia (P < 0AE05) 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 < 0AE0001 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 < 0AE01). 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.

Erythroid and megakaryocytic transformation

“…Another transcription factor that has been implicated in erythroid leukemia is the growth factor-independent 1B protein (GFI-1B). In a recent study, it was demonstrated that patients with AML M6 and AML M7 (acute megakaryocytic leukemia (AMKL, see below) express high levels of GFI-1B mRNA in bone marrow cells (Elmaagacli et al, 2007). Furthermore, this report also demonstrated a decrease in the proliferative capacity of K562 and HEL after silencing GFI-1B expression using siRNA.…”

“…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 vonWillebrand 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).…”

Additive antileukemia effects by GFI1B- and BCR–ABL-specific siRNA in advanced phase chronic myeloid leukemic cells

“…Primer and hybridization probes for RT-PCR for BCR-ABL, GFI1B, MDR1 and GAPDH have been previously published. 10,11,14 For p21…”

Associations between polymorphisms of the GFI1B gene and growth traits of indigenous Chinese goats

“…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.…”