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Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.


ABSTRACT: The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.

SUBMITTER: Chen W 

PROVIDER: S-EPMC2430522 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.

Chen Weili W   Kumar Ashish R AR   Hudson Wendy A WA   Li Quanzhi Q   Wu Baolin B   Staggs Rodney A RA   Lund Erik A EA   Sam Thien N TN   Kersey John H JH  

Cancer cell 20080501 5


The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP c  ...[more]

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