Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors.
Acute BCR-ABL expression during in vitro hematopoietic development of embryonic stem (ES) cells causes expansion of multipotent and myeloid progenitors with a concomitant reduction in differentiation toward erythroblasts. Progenitor cell expansion is due to a rapid, cell autonomous, suppression of programmed cell death with an increase in expression of the antiapoptotic molecule BCL-X(L). Other antiapoptotic effectors, including AKT, STAT5, and BCL-2 are not up-regulated by BCR-ABL in this system. In addition, the proapoptotic p38 mitogen-activated protein kinase (MAPK) pathway is suppressed by BCR-ABL expression in ES-derived hematopoietic progenitors. Inhibition of p38 MAPK by the small molecule inhibitor SB203580 expanded ES-derived hematopoietic progenitors by an antiapoptotic mechanism and is sufficient to expand ES-derived hematopoietic progenitors to levels approaching 80% of that seen following BCR-ABL expression. In the cellular context of ES-derived hematopoietic progenitors, BCR-ABL expression expands cells by suppressing programmed cell death with a set of antiapoptotic pathways distinct from those previously reported in continuous cell line studies.
Wong
Stephane
S
Molecular Biology Interdepartmental PhD Program, the Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, USA.
McLaughlin
Jami
J
Cheng
Donghui
D
Witte
Owen N
ON
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D017931:DNA Primers; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D016044:Fusion Proteins, bcr-abl