Malignant transformation initiated by Mll-AF9: gene dosage and critical target cells.
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.
Chen
Weili
W
University of Minnesota Cancer Center, University of Minnesota, 420 Delaware Street S.E., Minneapolis, MN 55455, USA.
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
D000818:Animals; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000166:cytology
C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein