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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Eduardo Anguita
  • Rajeev Gupta
  • Victor Olariu
  • Peter J Valk
  • Carsten Peterson
  • Ruud Delwel
  • Tariq Enver
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Medicinsk genetik
Originalspråkengelska
Sidor (från-till)277-286
TidskriftDevelopmental Biology
Volym411
Utgivningsnummer2
Tidigt onlinedatum2016 feb 3
StatusPublished - 2016
PublikationskategoriForskning
Peer review utfördJa