We identify a mutation (D262N) in the erythroid-affiliated transcriptional repressor GFI1B, in an acute myeloid leukemia (AML) patient with antecedent myelodysplastic syndrome (MDS). The GFI1B-D262N mutant functionally antagonizes the transcriptional activity of wild-type GFI1B. GFI1B-D262N promoted myelomonocytic versus erythroid output from primary human hematopoietic precursors and enhanced cell survival of both normal and MDS derived precursors. Re-analysis of AML transcriptome data identifies a distinct group of patients in whom expression of wild-type GFI1B and SPI1 (PU.1) have an inverse pattern. In delineating this GFI1B-SPI1 relationship we show that (i) SPI1 is a direct target of GFI1B, (ii) expression of GFI1B-D262N produces elevated expression of SPI1, and (iii) SPI1-knockdown restores balanced lineage output from GFI1B-D262N-expressing precursors. These results table the SPI1-GFI1B transcriptional network as an important regulatory axis in AML as well as in the development of erythroid versus myelomonocytic cell fate.

Acute myeloid leukemia, GFI1B, Myelodysplastic syndrome, PU.1, SPI1, Transcriptional networks
dx.doi.org/10.1016/j.ydbio.2016.02.002, hdl.handle.net/1765/81642
Developmental Biology
Erasmus MC: University Medical Center Rotterdam

Anguita, E, Gupta, R, Olariu, V, Valk, P.J.M, Peterson, C, Delwel, H.R, & Enver, T. (2016). A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network. Developmental Biology, 411(2), 277–286. doi:10.1016/j.ydbio.2016.02.002