OLIG2 (BHLHB1), a bHLH transcription factor, contributes to leukemogenesis in concert with LMO1.
OLIG2 (originally designated BHLHB1) encodes a transcription factor that contains the basic helix-loop-helix motif. Although expression of OLIG2 is normally restricted to neural tissues, overexpression of OLIG2 has been shown in patients with precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL). In the current study, we found that overexpression of OLIG2 was not only found in oligodendroglioma samples and normal neural tissue but also in a wide spectrum of malignant cell lines including leukemia, non-small cell lung carcinoma, melanoma, and breast cancer cell lines. To investigate whether enforced expression of OLIG2 is oncogenic, we generated transgenic mice that overexpressed OLIG2 in the thymus. Ectopic OLIG2 expression in the thymus was only weakly oncogenic as only 2 of 85 mice developed pre-T LBL. However, almost 60% of transgenic mice that overexpressed both OLIG2 and LMO1 developed pre-T LBL with large thymic tumor masses. Gene expression profiling of thymic tumors that developed in OLIG2/LMO1 mice revealed up-regulation of Notch1 as well as Deltex1 (Dtx1) and pre T-cell antigen receptor alpha (Ptcra), two genes that are considered to be downstream of Notch1. Of note, we found mutations in the Notch1 heterodimerization or proline-, glutamic acid-, serine-, and threonine-rich domain in three of six primary thymic tumors. In addition, growth of leukemic cell lines established from OLIG2/LMO1 transgenic mice was suppressed by a gamma-secretase inhibitor, suggesting that Notch1 up-regulation is important for the proliferation of OLIG2-LMO1 leukemic cells.
Lin
Ying-Wei
YW
Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20889-5105, USA.
Deveney
Ramona
R
Barbara
Mary
M
Iscove
Norman N
NN
Nimer
Stephen D
SD
Slape
Christopher
C
Aplan
Peter D
PD
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D010450:Endopeptidases; D020869:Gene Expression Profiling; D006801:Humans; D060588:LIM Domain Proteins; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D015513:Oncogene Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D060588:LIM Domain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D015513:Oncogene Proteins; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C065072:LMO1 protein, human; C513044:Lmo1 protein, mouse; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C405708:OLIG2 protein, human; C512773:Olig2 protein, mouse; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse