Forced expression of the Ikaros 6 isoform in human placental blood CD34(+) cells impairs their ability to differentiate toward the B-lymphoid lineage.
Studies in mice suggest that the Ikaros (Ik) gene encodes several isoforms and is a critical regulator of hematolymphoid differentiation. Little is known on the role of Ikaros in human stem cell differentiation. Herein, the biological consequences of the forced expression of Ikaros 6 (Ik6) in human placental blood CD34(+) progenitors are evaluated. Ik6 is one of the isoforms produced from the Ikaros premessenger RNA by alternative splicing and is thought to behave as a dominant negative isoform of the gene product because it lacks the DNA binding domain present in transcriptionally active isoforms. The results demonstrate that human cord blood CD34(+) cells that express high levels of Ik6 as a result of retrovirally mediated gene transfer have a reduced capacity to produce lymphoid B cells in 2 independent assays: (1) in vitro reinitiation of human hematopoiesis during coculture with the MS-5 murine stromal cell line and (2) xenotransplantation in nonobese diabetic-severe combined immunodeficient mice. These results suggest that Ikaros plays an important role in stem cell commitment in humans and that the balance between the different isoforms is a key element of this regulatory system; they support the hypothesis that posttranscriptional events can participate in the control of human hematopoietic differentiation.
Tonnelle
C
C
Institut Paoli-Calmettes, Centre Régional de Lutte Contre le Cancer Provence-Alpes-Côte d'Azur, Marseille, France. tonnellec@marseille.fnclcc.fr
Bardin
F
F
Maroc
C
C
Imbert
A M
AM
Campa
F
F
Dalloul
A
A
Schmitt
C
C
Chabannon
C
C
D000818:Animals; D018952:Antigens, CD34 / Q000097:blood*; D001402:B-Lymphocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D018920:Coculture Techniques; D004268:DNA-Binding Proteins; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D051740:Ikaros Transcription Factor; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012190:Retroviridae / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D018952:Antigens, CD34; D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D020033:Protein Isoforms; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor