A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network.

Summary, in English

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.

• Author: Eduardo Anguita; Rajeev Gupta; Victor Olariu; Peter J Valk; Carsten Peterson; Ruud Delwel; Tariq Enver
• Department/s: Computational Biology and Biological Physics - Has been reorganised
• Publishing year: 2016-02-03
• Language: English
• Pages: 277-286
• Publication/Series: Developmental Biology
• Volume: 411
• Issue: 2
• Links: http://dx.doi.org/10.1016/j.ydbio.2016.02.002
• Document type: Journal article
• Publisher: Elsevier
• Topic: Medical Genetics; Bioinformatics and Systems Biology; Other Physics Topics
• Status: Published
• Project: Computational Science for Health and Environment
• ISBN/ISSN/Other: ISSN: 1095-564X