Unknown,Transcriptomics,Genomics,Proteomics

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Comparison of the transcriptome of TEL-JAK2- versus activated NOTCH1 (ICN1)-induced T cell acute lymphoblastic leukemias (mouse)

ABSTRACT: The TEL-JAK2 fusion oncogene and the ICN1 activated allele of NOTCH1 are the result of specific chromosomal translocations in T cell acute lymphoblastic leukemia (T-ALL). Mouse models of these diseases (TEL-JAK2 transgenic mice; Carron C. et al. Blood (2000); a bone marrow transplantation model for ICN1-induced T-ALL) were used to compare the transcriptional program specific to each oncoprotein in mouse models of these leukemias. Tumor load was >50% leukemic cells in all selected organs. Leukemic cells were collected from the thymus of terminally-ill TEL-JAK2 leukemic mice and bone marrow of terminally-ill ICN1 leukemic mice. RNA was extracted from each sample and processed for hybridization to Affymetrix arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Jacques GHYSDAEL

PROVIDER: E-GEOD-51243 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Lymphotoxin-mediated activation of the lymphotoxin-Î² receptor (LTÎ²R) has been implicated in several physiological and pathological processes, including lymphoid organ development, T-cell maturation, and solid and hematopoietic malignancies. Its role in T-cell acute lymphoblastic leukemia (T-ALL) or other T-cell malignancies has remained however to be investigated. Here we show that the genes encoding lymphotoxin (LT)-Î± and LTÎ² were expressed in T-ALL patient samples, more abundantly in the TAL/LMO molecular subtype, and in the TEL-JAK2 mouse model of cortical/mature T-ALL. Surface LTÎ±1Î²2 protein was detected in primary mouse T-ALL cells, but only upon phorbol ester stimulation or absence of microenvironmental LTÎ²R interaction. Indeed, in contrast to leukemic cells collected from transplanted Ltbrâ/â mice or from co-cultures with Ltbrâ/â mouse embryonic fibroblasts (MEF), those collected from Ltbr+/+ mice or from Ltbr+/+ MEF co-cultures presented no surface LT expression. Supporting the notion that LT signaling plays a role in T-ALL, inactivation of the Ltbr gene in mice resulted in a statistically significant delay in TEL-JAK2-induced leukemia onset. Expression of the Lta and Ltb genes was found to be increased at the early asymtptomatic stages of TEL-JAK2 T-ALL, when only low proportions of malignant thymocytes are present in normal sized thymus. Interestingly, young asymptomatic TEL-JAK2;Ltbrâ/â mice presented significantly less leukemic thymocytes than TEL-JAK2;Ltbr+/+ mice. Together, these data indicate that early lymphotoxin expression by T-ALL cells activates LTÎ²R signaling in thymic stromal cells, thus promoting leukemogenesis. Primary T-ALL samples were obtained at diagnosis from bone marrow and/or peripheral blood with high leukemia involvement (>85%), and enriched by density centrifugation over Ficoll-Paque (GE Healthcare). Microarray analysis were performed on samples from patients with newly diagnosed T-ALL accrued from 2000 to 2013 at Centro Infantil Boldrini, Campinas, Brazil. Thymic samples, obtained from children undergoing cardiac surgery, were gently minced in culture medium and subsequently subjected to density centrifugation.

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Comparison of the transcriptome of TEL-JAK2- versus activated NOTCH1 (ICN1)-induced T cell acute lymphoblastic leukemias (mouse)

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