The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells

J Clin Invest. 2009 Apr;119(4):826-36. doi: 10.1172/JCI36428. Epub 2009 Mar 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Fetal Blood / cytology
  • Fetal Blood / metabolism
  • Gene Expression
  • Hematopoiesis / genetics
  • Humans
  • Mice
  • Models, Biological
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oncogene Fusion*
  • Oncogene Proteins, Fusion / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Precursor Cells, B-Lymphoid / metabolism*
  • Signal Transduction
  • Smad Proteins / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism
  • Transfection
  • Transforming Growth Factor beta / metabolism*


  • Cdkn1b protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • Oncogene Proteins, Fusion
  • Smad Proteins
  • TEL-AML1 fusion protein
  • Transforming Growth Factor beta
  • Cyclin-Dependent Kinase Inhibitor p27