GFI1(36N) as a therapeutic and prognostic marker for myelodysplastic syndrome.
Botezatu L., Michel LC., Makishima H., Schroeder T., Germing U., Haas R., van der Reijden B., Marneth AE., Bergevoet SM., Jansen JH., Przychodzen B., Wlodarski M., Niemeyer C., Platzbecker U., Ehninger G., Unnikrishnan A., Beck D., Pimanda J., Hellström-Lindberg E., Malcovati L., Boultwood J., Pellagatti A., Papaemmanuil E., Le Coutre P., Kaeda J., Opalka B., Möröy T., Dührsen U., Maciejewski J., Khandanpour C.
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. Because GFI1 regulates myeloid development, we examined the role of GFI1(36N) on the course of MDS disease. 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 United States. The GFI1(36N) allele frequency in the 723 MDS patients genotyped ranged between 9% and 12%. GFI1(36N) was an independent adverse prognostic factor for overall survival, acute myeloid leukemia-free survival, and event-free survival in a univariate analysis. After adjustment for age, bone marrow blast percentage, IPSS score, mutational status, and cytogenetic findings, GFI1(36N) remained an independent adverse prognostic marker. GFI1(36S) homozygous patients exhibited a sustained response to treatment with hypomethylating agents, whereas GFI1(36N) patients had a poor sustained response to this therapy. Because allele status of GFI1(36N) is readily determined using basic molecular techniques, we propose inclusion of GFI1(36N) status in future prospective studies for MDS patients to better predict prognosis and guide therapeutic decisions.