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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
; ; ; ; ; and
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
  • pmid:26851695
ISSN
1095-564X
DOI
10.1016/j.ydbio.2016.02.002
project
Computational Science for Health and Environment
language
English
LU publication?
yes
id
1899e547-7581-489f-be98-b0860c5f29b6 (old id 8829111)
date added to LUP
2016-04-01 10:52:48
date last changed
2024-04-07 19:16:45
@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}},
  doi          = {{10.1016/j.ydbio.2016.02.002}},
  volume       = {{411}},
  year         = {{2016}},
}