GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome (MDS)

Inherited gene variants play an important role in malignant diseases. The transcriptional repressor Growth factor independence 1 (GFI1) regulates hematopoietic stem cell (HSC) self-renewal and differentiation. A single nucleotide polymorphism of GFI1 (rs34631763) generates a protein with an asparagine (N) instead of a serine (S) at position 36 (GFI1(36N)) and has a prevalence of 3-5% among Caucasians. Since GFI1 regulates myeloid development, we examined the role of GFI1(36N) on MDS disease course. To this end, we determined allele frequencies of GFI1(36N) in four independent MDS cohorts from the Netherlands and Belgium, Germany, the ICGC consortium and the USA. The GFI1(36N) allele frequency in the 723 MDS patients genotyped ranged between 9-12%. GFI1(36N) was an independent adverse prognostic factor for overall survival, AML-free survival and event-free survival in an univariate analysis. After adjusting for age, bone marrow blast percentage, IPSS score, mutational status and cytogenetic findings, GFI1(36N) remained an independent adverse prognostic marker. With regard to therapy, whereas GFI1(36S) homozygous patients showed sustained response to treatment with hypomethylating agents, GFI1(36N) patients show poor sustained response to this therapy. Since allele status of GFI1(36N) is readily determined using basic molecular techniques, we propose to include GFI1(36N) status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions