Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes. HMGA2 (high-mobility group AT-hook 2) gene expression is extremely low in normal adult tissues, but it is overexpressed in many tumors. To identify the biological function of HMGA2, we generated transgenic mice carrying the human HMGA2 gene under control of the VH promoter/Eμ enhancer. Approximately 90% of Eμ-HMGA2 transgenic mice became visibly sick between 4 and 8 months due to the onset and progression of a T-ALL-like disease. Characteristic features included severe alopecia (30% of mice); enlarged lymph nodes and spleen; and profound immunological abnormalities (altered cytokine levels, hypoimmunoglobulinemia) leading to reduced immune responsiveness. Immunophenotyping showed accumulation of CD5+CD4+, CD5+CD8+ or CD5+CD8+CD4+ T-cell populations in the spleens and bone marrow of sick animals. These findings show that HMGA2-driven leukemia in mice closely resembles spontaneous human T-ALL, indicating that HMGA2 transgenic mice should serve as an important model for investigating basic mechanisms and potential new therapies of relevance to human T-ALL.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T cells that arises mainly in children and adolescents.[1]
Our two lines of Em-HMGA2 transgenic mice carrying the human HMGA2 gene under the control of the VH promoter/Em enhancer both developed lymphoproliferative disease bearing a strong resemblance to human T-ALL
The result is somewhat unexpected as the Em enhancer is considered to be a B-cell-specific enhancer, but it is able to drive the expression of linked gene(s) in
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of T cells that arises mainly in children and adolescents.[1]. T-ALL accounts for 10% of pediatric and 25% of adult T-cell lymphoma cases, and it is more common among males than in females.[1]. T-ALL patients show abnormal immune responses and levels of cytokines.[2]. It has been reported that T-ALL patients develop severe hypoimmunoglobulinemia.[3]. Malignant transformation of developing thymocytes is a multistep process caused by genetic abnormalities that alter the normal mechanisms of cell growth control, proliferation and differentiation.[1]. The genetic hallmark of T-ALL is translocation and aberrant expression of one or more transcription factors, such as TAL1, TAL2, LMO1, LMO2 and HOX11L2.1 NOTCH1 has an important role in substantial proportion of T-ALL cases, with activating mutations of NOTCH1 present in about 50% of T-ALL cases examined.[1]. All activating mutations are located in the heterodimerization domain and/or proline/glutamic acid/serine/ threonine PEST domain of NOTCH1.4 The majority of malignant
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