Mutant N-ras preferentially drives human CD34+ hematopoietic progenitor cells into myeloid differentiation and proliferation both in vitro and in the NOD/SCID mouse.
Exp Hematol
; 32(9): 852-60, 2004 Sep.
Article
em En
| MEDLINE
| ID: mdl-15345287
ABSTRACT
OBJECTIVES:
Ras oncogene mutations are the most frequently observed genetic abnormality (20-40% of patients) in acute myeloid leukemia (AML), and in the preleukemic conditions myelodysplastic syndrome (MDS) and myeloproliferative disorder (MPD). We have previously shown that mutant N-ras (N-rasm) can induce myeloproliferative disorders and apoptosis in a murine reconstitution system. In the present study we investigated the effect of N-rasm in human primary hematopoietic progenitor cells (HPC).METHODS:
Cord blood CD34+ hematopoietic progenitor cells (HPC) were transduced with retroviral vectors containing green fluorescence protein (GFP) alone, or in combination with N-rasm. Cells were then cultured in vitro with a cytokine supplement or cocultured with murine stroma MS-5 cells. The in vivo behavior of transduced cells was examined in the NOD/SCID mouse model.RESULTS:
N-rasm-transduced cells exhibited greater proliferative capacity; a higher frequency of granulocyte-macrophage colony-forming unit (CFU-GM); and an increase in myelomonocytic lineage cells with a concomitant decrease in lymphoid and erythroid cells. Analysis of transduced HPC in NOD/SCID mice revealed higher bone marrow engraftment by N-rasm HPC and increased numbers of myeloid lineage cells.CONCLUSIONS:
The results demonstrate that N-rasm in HPC induces myeloproliferation both in vitro and in the NOD/SCID mouse model as a primary event that does not appear to be dependent on cooperating transforming events.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
/
Genes ras
/
Antígenos CD34
/
Células Mieloides
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Exp Hematol
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Austrália