The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.
Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-beta. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-beta. Further analysis indicated that TEL-AML1 binds to a principal TGF-beta signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-beta-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38-CD19+) and a marked growth advantage in the presence of TGF-beta. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.
Ford
Anthony M
AM
Section of Haemato-Oncology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Palmi
Chiara
C
Bueno
Clara
C
Hong
Dengli
D
Cardus
Penny
P
Knight
Deborah
D
Cazzaniga
Giovanni
G
Enver
Tariq
T
Greaves
Mel
M
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051379:Mice; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015514:Oncogene Proteins, Fusion; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C493961:Cdkn1b protein, mouse; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein