Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia

The TEL-JAK2 gene fusion, which has been identified in human leukemia, encodes a chimeric protein endowed with constitutive tyrosine kinase activity. TELJAK2 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 ESR-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. TELJAK2 transforms immature CD4CD8 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-, CD3- and pT-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 TCR transgene that mimics pre-TCR signaling. Although not affecting leukemia incidence and mouse survival, TCR expression was shown to facilitate leukemic cell expansion in secondary lymphoid organs. (Blood. 2007;109:3972-3981)