A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network
Developmental Biology , Volume 411 - Issue 2 p. 277- 286
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|
|Organisation||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