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| Status |
Public on Mar 04, 2019 |
| Title |
The oncoprotein NUP98-HOXD13 (NHD13) induces thymocyte self-renewal via Lmo2/Lyl1 |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
T-cell Acute Lymphoblastic Leukaemia (T-ALL) can be classified into a number of subfamilies, including those that overexpress TAL1/LMO, TLX1/3 and HOXA transcription factors. Whilst it has been previously shown in mouse models that TAL1/LMO transcription factors induce thymocyte self-renewal, whether this is the case for other transcription factor subclasses is currently unknown. To address this, we have studied vav-Nup98-HoxD13-transgenic (NHD13-Tg) mice, a model of HOXA-driven T-ALL, which overexpress HOXA transcription factors throughout haematopoiesis and display features of myelodysplastic syndrome in the bone marrow along with T-cell developmental abnormalities in the thymus and subsequent development of T-ALL in approximately 15% of mice. Thymocytes from preleukemic NHD13-Tg mice could engraft long-term in serial transplantation assays, demonstrating that NHD13-Tg thymocytes have acquired self-renewal capacity. Transcriptome analysis showed that NHD13-Tg thymocytes exhibited a Stem Cell like transcriptional program which closely resembled that of Lmo2 transgenic thymocytes, including Lmo2 itself and the critical Lmo2 cofactor Lyl1, suggesting a common mechanism of thymocyte self-renewal in these models. To determine whether Lmo2/Lyl1 are required for NHD13-induced thymocyte self-renewal, NHD13-Tg mice were crossed with Lyl1 knockout mice to generate NHD13-Tg mice lacking Lyl1. This showed that Lyl1 is essential for expression of the stem cell-like gene expression program in NHD13-Tg thymocytes and for thymocyte self-renewal. Surprisingly however, absence of Lyl1 accelerated the onset of T-ALL in NHD13-Tg mice. These studies demonstrate that Lyl1 is essential for self-renewal of NHD13-Tg thymocytes, suggesting that Lmo2 and Lyl1 may mediate thymocyte self-renewal induced by a variety of T-cell oncogenes. However, whilst Lyl1-induced thymocyte self-renewal is essential for Lmo2-driven T-cell leukemia, NHD13 can also promote T-ALL via an alternative pathway.
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| Overall design |
Total RNA obtained from sorted CD4-CD8 double-negative thymocytes
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| Contributor(s) |
Shields BJ, Shi W, McCormack MP |
| Citation(s) |
30700838 |
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| Submission date |
Oct 22, 2018 |
| Last update date |
Mar 04, 2019 |
| Contact name |
Wei Shi |
| E-mail(s) |
Wei.Shi2@monash.edu
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| Organization name |
Monash University
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| Street address |
Wellington Rd
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| City |
Clayton |
| State/province |
Victoria |
| ZIP/Postal code |
3800 |
| Country |
Australia |
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| Platforms (1) |
| GPL6887 |
Illumina MouseWG-6 v2.0 expression beadchip |
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| Samples (12)
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| GSM3440889 |
Sample4_Wild-type DN thymocytes rep 4 |
| GSM3440890 |
Sample5_Wild-type DN thymocytes rep 5 |
| GSM3440891 |
Sample6_Wild-type DN thymocytes rep 6 |
| GSM3440892 |
Sample7_NHD13 transgenic DN thymocytes rep 1 |
| GSM3440893 |
Sample8_NHD13 transgenic DN thymocytes rep 2 |
| GSM3440894 |
Sample9_NHD13 transgenic DN thymocytes rep 3 |
| GSM3440895 |
Sample10_NHD13 transgenic, Lyl1 knockout DN thymocytes rep 1 |
| GSM3440896 |
Sample11_NHD13 transgenic, Lyl1 knockout DN thymocytes rep 2 |
| GSM3440897 |
Sample12_NHD13 transgenic, Lyl1 knockout DN thymocytes rep 3 |
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| Relations |
| BioProject |
PRJNA497916 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE121641_RAW.tar |
15.8 Mb |
(http)(custom) |
TAR |
| GSE121641_non_normalized.txt.gz |
2.3 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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