Unknown,Transcriptomics,Genomics,Proteomics

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Expression Analysis of Whole Thymus and Thymic Tumors on the Sdl Mouse Model

ABSTRACT: Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance; while mice homozygous for the mutation die early during embryonic development. Sdl mice harbor increased numbers of spontaneous micronuclei, and Sdl T-ALLs harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4D573H). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at the replication fork. This exon array was conducted to determine the expression changes that occur in pre-leukemic thymus samples at 21 days of age, as well as thymic tumors in the Sdl model. generated pairwise comparisons of wild-type > pre-leukemic and wild-type > thymic tumor. Transcripts with a posterior probability of differential expression >95% and a q-value < 0.05 were considered to be significantly differentially expressed.

ORGANISM(S): Mus musculus

SUBMITTER: Bruce Bagley

PROVIDER: E-GEOD-40527 | 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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Expression Analysis of Whole Thymus and Thymic Tumors on the Sdl Mouse Model

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