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Human HMGA2 protein overexpressed in mice induces precursor T-cell lymphoblastic leukemia.

Efanov A, Zanesi N, Coppola V, Nuovo G, Bolon B, Wernicle-Jameson D, Lagana A, Hansjuerg A, Pichiorri F, Croce CM - Blood Cancer J (2014)

Bottom Line: T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, College of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

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.

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(a) Eμ-HMGA2 construct. (b) HMGA2 expression in B and T cells of two transgenic lines. Western blot analysis was carried out using anti-HA antibodies. WT spleen lysate from a wild-type FVB/N mouse. F9 and F28 spleen lysates from F9 and F28 transgenic lines correspondingly. (c) Gross pathology of a representative 5-month-old Eμ-HMGA2 transgenic mouse, exhibiting greatly enlarged lymph nodes (arrows) and spleen relative to a wild-type of the same age. (d) A representative Eμ-HMGA2 transgenic mouse with severe skin lesion (right) and wild-type counterpart (left).
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fig1: (a) Eμ-HMGA2 construct. (b) HMGA2 expression in B and T cells of two transgenic lines. Western blot analysis was carried out using anti-HA antibodies. WT spleen lysate from a wild-type FVB/N mouse. F9 and F28 spleen lysates from F9 and F28 transgenic lines correspondingly. (c) Gross pathology of a representative 5-month-old Eμ-HMGA2 transgenic mouse, exhibiting greatly enlarged lymph nodes (arrows) and spleen relative to a wild-type of the same age. (d) A representative Eμ-HMGA2 transgenic mouse with severe skin lesion (right) and wild-type counterpart (left).

Mentions: We generated transgenic mice bearing the human HMGA2 gene with 3′-HA under the control of the VH promoter/Eμ enhancer with the poly(A) site of the human globin gene (Figure 1a). The Eμ enhancer specifically drives expression in B cells, but also is active in T cells.13 We selected two founders and entitled them F9 and F28. These founders were bred with wild-type FVB/N mice to establish two transgenic lines. Expression of HMGA2 was determined by western blot in B- and T-splenocyte protein lysates using anti-HA antibody. Figure 1b shows high HMGA2 expression in T cells of both lines and moderate expression in B cells.


Human HMGA2 protein overexpressed in mice induces precursor T-cell lymphoblastic leukemia.

Efanov A, Zanesi N, Coppola V, Nuovo G, Bolon B, Wernicle-Jameson D, Lagana A, Hansjuerg A, Pichiorri F, Croce CM - Blood Cancer J (2014)

(a) Eμ-HMGA2 construct. (b) HMGA2 expression in B and T cells of two transgenic lines. Western blot analysis was carried out using anti-HA antibodies. WT spleen lysate from a wild-type FVB/N mouse. F9 and F28 spleen lysates from F9 and F28 transgenic lines correspondingly. (c) Gross pathology of a representative 5-month-old Eμ-HMGA2 transgenic mouse, exhibiting greatly enlarged lymph nodes (arrows) and spleen relative to a wild-type of the same age. (d) A representative Eμ-HMGA2 transgenic mouse with severe skin lesion (right) and wild-type counterpart (left).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4219444&req=5

fig1: (a) Eμ-HMGA2 construct. (b) HMGA2 expression in B and T cells of two transgenic lines. Western blot analysis was carried out using anti-HA antibodies. WT spleen lysate from a wild-type FVB/N mouse. F9 and F28 spleen lysates from F9 and F28 transgenic lines correspondingly. (c) Gross pathology of a representative 5-month-old Eμ-HMGA2 transgenic mouse, exhibiting greatly enlarged lymph nodes (arrows) and spleen relative to a wild-type of the same age. (d) A representative Eμ-HMGA2 transgenic mouse with severe skin lesion (right) and wild-type counterpart (left).
Mentions: We generated transgenic mice bearing the human HMGA2 gene with 3′-HA under the control of the VH promoter/Eμ enhancer with the poly(A) site of the human globin gene (Figure 1a). The Eμ enhancer specifically drives expression in B cells, but also is active in T cells.13 We selected two founders and entitled them F9 and F28. These founders were bred with wild-type FVB/N mice to establish two transgenic lines. Expression of HMGA2 was determined by western blot in B- and T-splenocyte protein lysates using anti-HA antibody. Figure 1b shows high HMGA2 expression in T cells of both lines and moderate expression in B cells.

Bottom Line: T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasia of thymocytes characterized by the rapid accumulation of the precursors of T lymphocytes.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, College of Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

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.

Show MeSH
Related in: MedlinePlus