Abstract
Transcription factor Growth Factor Independence 1 (GFI1) regulates the expression of genes important for survival, proliferation and differentiation of hematopoietic cells. A single nucleotide polymorphism (SNP) variant of GFI1 (GFI1-36N: serine replaced by asparagine at position 36), has a prevalence of 5-7% among healthy Caucasians and 10-15% in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) predisposing GFI-36N carriers to these diseases. Since GFI1 is implicated in B cell maturation and plasma cell (PC) development, we examined its prevalence in patients with multiple myeloma (MM), a haematological malignancy characterized by expansion of clonal PCs. Strikingly, as in MDS and AML, we found that the GFI1-36N had a higher prevalence among MM patients compared to the controls. In subgroup analyses, GFI1-36N correlates to a shorter overall survival of MM patients characterized by the presence of t(4;14) translocation and gain of 1q21 (≤3 copies). MM patients carrying gain of 1q21 (≥3 copies) demonstrated poor progression free survival. Furthermore, gene expression analysis implicated a role for GFI1-36N in epigenetic regulation and metabolism, potentially promoting the initiation and progression of MM.
Highlights
Growth Factor Independence 1 (GFI1) is a zinc-finger transcriptional repressor with an essential role in controlling hematopoietic stem cell biology, myeloid and lymphoid differentiation and lymphocyte effector functions
We previously reported that a coding single nucleotide polymorphism (SNP) in the human GFI1 predisposes carriers to myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) and influenced their prognosis [3, 4]
We determined the frequency of germline GFI1-36N homo- or heterozygous carriers among a cohort of 1229 newly diagnosed MM patients and 2005 unaffected control persons based on published genome-wide association study (GWAS) data of patients treated within the German-Speaking Myeloma Multicenter Group (GMMG), HD3, HD4 and MM5 trials
Summary
GFI1 is a zinc-finger transcriptional repressor with an essential role in controlling hematopoietic stem cell biology, myeloid and lymphoid differentiation and lymphocyte effector functions. The establishment of murine models with constitutive and conditional loss of Gfi expression enabled visualization of their cell-specific expression and understanding of Gfi function in hematopoietic lineages [1]. GFI1 exerts its function as a transcriptional repressor by recruiting histone-modifying enzymes to its target genes [2]. Genome-wide H3K9-acetylation level of GFI1 target genes was increased in hematopoietic progenitor cells of GFI1-36N mice and primary murine and human GFI136N leukemic cells [3]. Higher H3K9-acetylation of the genes in GFI1-36N-expressing cells correlated with higher expression and activation of genes facilitating AML development [3]
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