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| Status |
Public on Aug 16, 2012 |
| Title |
Burkitt Lymphoma Pathogenesis and Therapeutic Targets from Structural and Functional Genomics |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Burkitt lymphoma (BL) can often be cured by intensive chemotherapy, but the toxicity of such therapy precludes its use in the elderly and in patients with endemic BL (eBL) in developing countries, necessitating new strategies. The normal germinal center B cell is the presumed cell of origin for both BL and diffuse large B cell lymphoma (DLBCL), yet gene expression analysis suggests that these malignancies may utilize different oncogenic pathways. BL is subdivided into a sporadic subtype (sBL) that is diagnosed in developed countries, the EBV-associated eBL subtype, and an HIV-associated subtype (hivBL), but it is unclear whether these subtypes employ similar or divergent oncogenic mechanisms. Here we used high throughput RNA sequencing and RNA interference screening to discover essential regulatory pathways that cooperate with MYC, the defining oncogene of this cancer. In 70% of sBL cases, mutations affecting the transcription factor TCF3 (E2A) or its negative regulator ID3 fostered TCF3 dependency. TCF3 activated the pro-survival PI(3) kinase pathway in BL, in part by augmenting tonic B cell receptor signaling. In 38% of sBL cases, oncogenic CCND3 mutations produced highly stable cyclin D3 isoforms that drive cell cycle progression. These findings suggest opportunities to improve therapy for patients with BL.
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| Overall design |
Gene expression was analyzed using Agilent human 4X44K oligo gene expression arrays. Cell lines (Namalwa, BL41, Daudi, Defauw, and THOMAS) were infected with control (empty vector, Cy3) paired with ID3 (Cy5) or control (shControl, Cy3) paired with shTCF3 (Cy5) constructs, and changes in gene expression were monitored over time after induction of the constructs with doxycyclin. In Namalwa (n=8) and THOMAS (n=4) cell lines, a four timepoint series (24, 48, 72, 96 hours) of construct induction was analyzed, for a total of 12 arrays. In BL41 (n=4), Daudi (n=4) and Defauw (n=4) cell lines, a two timepoint series (24 and 48 hours) of construct induction was analyzed, for a total of 12 arrays. In addition, two cell lines (Daudi and THOMAS) were treated with Rapamycin (100 pM) and paired with a DMSO control in a four timepoint series (3, 6, 12 and 24 hours) for a total of 8 arrays.
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| Citation(s) |
22885699 |
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| Submission date |
Jan 17, 2012 |
| Last update date |
Feb 22, 2018 |
| Contact name |
Louis M. Staudt |
| E-mail(s) |
lstaudt@mail.nih.gov
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| Phone |
301-402-1892
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| Organization name |
National Cancer Institute
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| Department |
Lymphoid Malignancies Branch
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| Lab |
Louis M Staudt
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| Street address |
9000 Rockville Pike, Bldg 10, Rm 4N114
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
| GPL4133 |
Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version) |
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| Samples (32)
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| GSM862847 |
THOMAS shTCF3 - 24 hours - mAdbID:117406 |
| GSM862848 |
THOMAS shTCF3 - 48 hours - mAdbID:117407 |
| GSM862849 |
THOMAS shTCF3 - 72 hours - mAdbID:117408 |
| GSM862850 |
THOMAS shTCF3 - 96 hours - mAdbID:117409 |
| GSM862851 |
Namalwa ID3 - 24 hours - mAdbID:117526 |
| GSM862852 |
Namalwa ID3 - 48 hours - mAdbID:117527 |
| GSM862853 |
Namalwa ID3 - 72 hours - mAdbID:117528 |
| GSM862854 |
Namalwa ID3 - 96 hours - mAdbID:117529 |
| GSM862855 |
Namalwa shTCF3 - 24 hours - mAdbID:117530 |
| GSM862856 |
Namalwa shTCF3 - 48 hours - mAdbID:117531 |
| GSM862857 |
Namalwa shTCF3 - 72 hours - mAdbID:117532 |
| GSM862858 |
Namalwa shTCF3 - 96 hours - mAdbID:117533 |
| GSM862859 |
Daudi shTCF3 - 24 hours - mAdbID:117716 |
| GSM862860 |
Daudi shTCF3 - 48 hours - mAdbID:117717 |
| GSM862861 |
Daudi ID3 - 24 hours - mAdbID:117718 |
| GSM862862 |
Daudi ID3 - 48 hours - mAdbID:117719 |
| GSM862863 |
BL41 shTCF3 - 24 hours - mAdbID:117720 |
| GSM862864 |
BL41 shTCF3 - 48 hours - mAdbID:117721 |
| GSM862865 |
BL41 ID3 - 24 hours - mAdbID:117722 |
| GSM862866 |
BL41 ID3 - 48 hours - mAdbID:117723 |
| GSM862867 |
Defauw shTCF3 - 24 hours - mAdbID:117724 |
| GSM862868 |
Defauw shTCF3 - 48 hours - mAdbID:117725 |
| GSM862869 |
Defauw ID3 - 24 hours - mAdbID:117726 |
| GSM862870 |
Defauw ID3 - 48 hours - mAdbID:117727 |
| GSM960117 |
Daudi Rapamycin - 3 hours - mAdbID:118706 |
| GSM960118 |
Daudi Rapamycin - 6 hours - mAdbID:118707 |
| GSM960119 |
Daudi Rapamycin - 12 hours - mAdbID:118708 |
| GSM960120 |
Daudi Rapamycin - 24 hours - mAdbID:118709 |
| GSM960121 |
THOMAS Rapamycin - 3 hours - mAdbID:118710 |
| GSM960122 |
THOMAS Rapamycin - 6 hours - mAdbID:118711 |
| GSM960123 |
THOMAS Rapamycin - 12 hours - mAdbID:118712 |
| GSM960124 |
THOMAS Rapamycin - 24 hours - mAdbID:118713 |
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| Relations |
| BioProject |
PRJNA150793 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE35163_RAW.tar |
457.3 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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