Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of CA10 and NHD13 murine AML

ABSTRACT: We have compared the gene expression profiles of leukemic tissues in two different mouse models of AML, CALM-AF10 and NHD13, to clincally healthy transgenic and wildtype hematopoetic tissue to identify genes and pathways that can collaborate with these oncogenic fusion proteins to promote leukemic transformation. CA10 and NHD13 transgenic mice were sacrificed when clinical signs of leukemia manifested (mice were hunched, skinny, or had an abnormal complete blood count). For comparsion, we harvested age matched bone marrow, thymi, and spleen from wildtype and clinically healthy trangenic tissues. Transgenic animals were considered clinically healthy if no evident signs of leukemia were present.

ORGANISM(S): Mus musculus

SUBMITTER: Rachel Novak

PROVIDER: E-GEOD-40531 | 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.

Project description:It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. To this end, we studied a mouse model of human T cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single cell level over time. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across, and proliferated within multiple bone marrow sub-compartments. Unexpectedly, this environment-agnostic behaviour was maintained throughout disease development, starting from the earliest bone marrow seeding to the response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting a stochastic mechanism underlies these processes. Yet, while T-ALL infiltration and progression are niche-independent, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells whilst perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function1. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo highlights that future therapeutic interventions should target cancer cell-intrinsic mechanisms, rather than signals from specific bone marrow stroma, in order to combat the invasion by and survival of chemo-resistant T-ALL cells. Notch-1 T-ALL tumours were generated as previously described in (Hawkins et al., PLoS One, 2014 - doi: 10.1371/journal.pone.0087376.).The T-ALL mouse model was generated by retroviral transduction of C57Bl/6 E14.5 fetal liver cells as described in (Hawkins et al., PLoS One, 2014 - doi: 10.1371/journal.pone.0087376.). Whole transduced populations were transplanted into 8-14 week old female C57Bl/6 recipient mice. T cell acute lymphoblastic leukemia cells were positive for the fluorescent protein (GFP or DsRed) indicating expression of the Notch-1 intracellular protein. These tumours were most frequently CD4+8+ as originally described in (Aster, J. C. et al. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Molecular and cellular biology 20, 7505-7515 (2000). Disease was confirmed by flow cytometry and 2-photon imaging. Mice reconstituted with Notch transduced foetal livers were monitored daily for signs of leukaemia onset or other signs of ill health. Tumours were harvested from bone marrow once full infiltration was established as confirmed by peripheral blood and bone marrow flow cytometry as well as 2-photon imaging. For treated samples, dexamethasone (Dexamethasone Sodium Phosphate - Sigma) was administered daily I.V. - 15mg/kg for 7 days. Tumours were isolated purified from bone marrow by FACS sorting based on expression of fluorescent protein expression (GFP+ or DsRed+).

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Gene expression profiling of CA10 and NHD13 murine AML

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