In vitro-generated stem cell leukaemia showing altered cell cycle progression with distinct signalling of the tyrosine-phosphorylated rasGAP-associated p62dok protein
✍ Scribed by Ralf Huss; Eva M. Weissinger; Claudia Lange; Petros Gatsios; Günther Eissner; Hans-Jochem Kolb; Joachim Diebold; Peter C. Heinrich; Lutz Graeve
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 350 KB
- Volume
- 192
- Category
- Article
- ISSN
- 0022-3417
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✦ Synopsis
In an attempt to gain more insight into the events of leukaemic transformation, a cell line overexpressing MHC class II (DR) was generated by transfecting an early CD34-negative haematopoietic progenitor stem cell line with the appropriate constructs. The stable transfection with genes for DR antigens leads to cellular transformation. The DR + transformed cell clones express a tyrosine-phosphorylated DR heterodimer and show a signi®cantly different morphology. DR + clones present the morphology of an immature myeloid neoplasia expressing a-naphthylacetate-esterase (ANAE), but neither myeloperoxidase nor CD34. While D064 cells predominately grow adherent as ®broblast-like cells, the DR + clones display a decrease in adherent growth. Although both cell lines express similar amounts of the interleukin-6 (IL-6) signal transducer gp130, the DR-transfected cells still show activation of STAT factors by IL-6, whereas D064 cells do not. Although the transformed clones present acceleration of cell-cycle transition and growth, the G 0 /G 1 progression inhibitor p27 kip-1 is up-regulated, while the expression of proteins involved in the S/G 2 phase transition, such as cyclin B and cdc2 (p34), is suppressed. Instead cyclin D3, one of the G 0 /G 1 progression factors, is up-regulated, as well as tyrosinephosphorylated p62 dok , suggesting dysregulation of cell cycle-controlling proteins. In addition, DR + leukaemia-like cells also overexpress Bcl-2, while bax expression is suppressed, compared with the wild-type (wt) parental haematopoietic stem cell line.