title: A somatic mutation of GFI1B identified in leukemia alters cell fate via a SPI1 (PU.1) centered genetic regulatory network.
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.
authors: Hematology Department, Hospital Clínico San Carlos (IdISSC), Prof. Martín Lagos s/n, 28040 Madrid, Spain. Electronic address: eduardo.anguita@salud.madrid.org.
authors: Eduardo
authors: E
authors: Anguita
authors: UCL Cancer Institute, Paul O'Gorman Building 72 Huntley St., London WC1E6BT, United Kingdom. Electronic address: rajeev.gupta@ucl.ac.uk.
authors: Rajeev
authors: R
authors: Gupta
authors: Computational Biology and Biological Physics Division, Lund University, Lund, Sweden. Electronic address: victor.olariu@thep.lu.se.
authors: Victor
authors: V
authors: Olariu
authors: Department of Hematology Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: p.valk@erasmusmc.nl.
authors: Peter J
authors: PJ
authors: Valk
authors: Computational Biology and Biological Physics Division, Lund University, Lund, Sweden. Electronic address: carsten@thep.lu.se.
authors: Carsten
authors: C
authors: Peterson
authors: Department of Hematology Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: h.delwel@erasmusmc.nl.
authors: Ruud
authors: R
authors: Delwel
authors: UCL Cancer Institute, Paul O'Gorman Building 72 Huntley St., London WC1E6BT, United Kingdom. Electronic address: t.enver@ucl.ac.uk.
authors: Tariq
authors: T
authors: Enver
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D053263:Gene Regulatory Networks; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018952:Antigens, CD34; D016179:Granulocyte Colony-Stimulating Factor; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C111977:GFI1B protein, human
keywords: Acute myeloid leukemia; GFI1B; Myelodysplastic syndrome; PU.1; SPI1; Transcriptional networks