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

Anguita, Eduardo; Gupta, Rajeev; Olariu, Victor LU ; Valk, Peter J; Peterson, Carsten LU ; Delwel, Ruud and Enver, Tariq (2016) In Developmental Biology 411(2). p.277-286
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Developmental Biology
volume
411
issue
2
pages
277 - 286
publisher
Elsevier
external identifiers
  • pmid:26851695
  • scopus:84959462004
  • wos:000372383500011
ISSN
1095-564X
DOI
10.1016/j.ydbio.2016.02.002
language
English
LU publication?
yes
id
1899e547-7581-489f-be98-b0860c5f29b6 (old id 8829111)
date added to LUP
2016-03-04 09:40:15
date last changed
2017-04-23 03:18:41
@article{1899e547-7581-489f-be98-b0860c5f29b6,
  abstract     = {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       = {Anguita, Eduardo and Gupta, Rajeev and Olariu, Victor and Valk, Peter J and Peterson, Carsten and Delwel, Ruud and Enver, Tariq},
  issn         = {1095-564X},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {277--286},
  publisher    = {Elsevier},
  series       = {Developmental Biology},
  title        = {A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network.},
  url          = {http://dx.doi.org/10.1016/j.ydbio.2016.02.002},
  volume       = {411},
  year         = {2016},
}