Journal
DEVELOPMENTAL BIOLOGY
Volume 411, Issue 2, Pages 277-286Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ydbio.2016.02.002
Keywords
GFI1B; SPI1; PU.1; Transcriptional networks; Acute myeloid leukemia; Myelodysplastic syndrome
Categories
Funding
- Spanish Ministry of Science [SAF2005-04709]
- Madrid Regional Government/UCM [CCG08-UCM/BIO-3997]
- LLR
- MRC Molecular Hematology Unit Intramural Programme
- UCL CBRC
- BLUEPRINT (UK)
- Ramon y Cajal grant [2570594457 Y200200074]
- Jose Castillejo program (JC) [2008-00022]
- SEHH
- ICRETT [ICR/09/102]
- Swedish Foundation for Strategic Research [A3 06:215]
- MRC [MR/N000838/1, MR/M009033/1, MC_U137973817] Funding Source: UKRI
- Cancer Research UK [12796] Funding Source: researchfish
- Medical Research Council [MC_U137973817, G1000801g, MR/N000838/1, MR/M009033/1] Funding Source: researchfish
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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 SPIT (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) SPIT-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. (C) 2016 Published by Elsevier Inc.
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