title: Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia.
abstract: The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TEL-JAK2 transgenic expression in the mouse lymphoid lineage results in fatal and rapid T-cell leukemia/lymphoma. In the present report we show that T-cell leukemic cells from EmuSRalpha-TEL-JAK2 transgenic mice present an aberrant CD8(+) differentiation phenotype, as determined by the expression of stage-specific cell surface markers and lineage-specific genes. TEL-JAK2 transforms immature CD4(-)CD8(-) double-negative thymocytes, as demonstrated by the development of T-cell leukemia with full penetrance in a Rag2-deficient genetic background. This disease is similar to the bona fide TEL-JAK2 disease as assessed by phenotypic and gene profiling analyses. Pre-TCR signaling synergizes with TEL-JAK2 to transform immature thymocytes and initiate leukemogenesis as shown by (1) the delayed leukemia onset in Rag2-, CD3epsilon- and pTalpha-deficient mice, (2) the occurrence of recurrent chromosomal alterations in pre-TCR-deficient leukemia, and (3) the correction of delayed leukemia onset in Rag2-deficient TEL-JAK2 mice by an H-Y TCRalphabeta transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCRalphabeta expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs.
authors.affiliation: Centre de Recherche, Institut Curie, F-91405 Orsay, France.
authors.forename: Nuno R
authors.initials: NR
authors.lastname: dos Santos
authors.forename: David S
authors.initials: DS
authors.lastname: Rickman
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reynies
authors.forename: Françoise
authors.initials: F
authors.lastname: Cormier
authors.forename: Maryvonne
authors.initials: M
authors.lastname: Williame
authors.forename: Camille
authors.initials: C
authors.lastname: Blanchard
authors.forename: Marc-Henri
authors.initials: MH
authors.lastname: Stern
authors.forename: Jacques
authors.initials: J
authors.lastname: Ghysdael
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D015514:Oncogene Proteins, Fusion; D016693:Receptors, Antigen, T-Cell, alpha-beta; C491568:TEL-JAK2 fusion protein, mouse; D053614:Janus Kinase 2; D000097764:ETS Translocation Variant 6 Protein