Unknown,Transcriptomics,Genomics,Proteomics

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LMO2 expression in HSCs causes T-ALL in the presence of an intact thymic niche [nude mice]

ABSTRACT: We used microarrays to investigate gene expression changes in tumor-bearing Sca1-TOMATO-Lmo2 Nu/Nu mice Tumor-bearing bone marrows of three Sca1-TOMATO-Lmo2 Nu/Nu mice compared with bone marrow cells from four Control Nude mice and with thymus leukemic cells from ten Sca1-TOMATO-Lmo2 mice. GSM2209767 - GSM2209776 are re-analyses of GSE83570 (GSM2209749 - GSM220975 and GSM2209757 - GSM2209759).

ORGANISM(S): Mus musculus

SUBMITTER: Isidro SÃ¡nchez GarcÃa

PROVIDER: E-GEOD-83571 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description: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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LMO2 expression in HSCs causes T-ALL in the presence of an intact thymic niche [nude mice]

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