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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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Related in: MedlinePlus

(a) The levels of immunoglobulins in 5–8-month-old Eμ-HMGA2 transgenic mice are much lower to those of age-matched wild-type control mice. (b) Production of anti-KHL antibodies as indicated by circulating serum levels in transgenic mice was lower than that of wild-type counterparts. (c) The levels of tumor necrosis factor alpha and IL-6 in serum of Eμ-HMGA2 transgenic mice were greatly elevated relative to those of their wild-type littermates.
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fig5: (a) The levels of immunoglobulins in 5–8-month-old Eμ-HMGA2 transgenic mice are much lower to those of age-matched wild-type control mice. (b) Production of anti-KHL antibodies as indicated by circulating serum levels in transgenic mice was lower than that of wild-type counterparts. (c) The levels of tumor necrosis factor alpha and IL-6 in serum of Eμ-HMGA2 transgenic mice were greatly elevated relative to those of their wild-type littermates.

Mentions: Human T-ALL is characterized by immune incompetence, abnormal cytokine production and severe hypogammaglobulinemia.2, 3 Serum levels of immunoglobulins in Eμ-HMGA2 transgenic mice were severely decreased relative to those in wild-type littermates (Figure 5a), including IgG1, IgG2a, IgG2b and IgG3. The levels of IgG1 were decreased by about threefold, and the levels of IgG2a, IgG2b and IgG3 by 3.5-fold. In contrast, there was no difference in IgA levels. The ability of HMGA2 transgenic mice to mount an immune response to an antigen KHL was reduced by about threefold in comparison with wild-type counterparts (Figure 5b). Serum levels of IL-6 were sixfold higher and those of tumor necrosis factor alpha levels were 10-fold higher in HMGA2 transgenic animals compared with wild-type counterparts (Figure 5c).


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) The levels of immunoglobulins in 5–8-month-old Eμ-HMGA2 transgenic mice are much lower to those of age-matched wild-type control mice. (b) Production of anti-KHL antibodies as indicated by circulating serum levels in transgenic mice was lower than that of wild-type counterparts. (c) The levels of tumor necrosis factor alpha and IL-6 in serum of Eμ-HMGA2 transgenic mice were greatly elevated relative to those of their wild-type littermates.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: (a) The levels of immunoglobulins in 5–8-month-old Eμ-HMGA2 transgenic mice are much lower to those of age-matched wild-type control mice. (b) Production of anti-KHL antibodies as indicated by circulating serum levels in transgenic mice was lower than that of wild-type counterparts. (c) The levels of tumor necrosis factor alpha and IL-6 in serum of Eμ-HMGA2 transgenic mice were greatly elevated relative to those of their wild-type littermates.
Mentions: Human T-ALL is characterized by immune incompetence, abnormal cytokine production and severe hypogammaglobulinemia.2, 3 Serum levels of immunoglobulins in Eμ-HMGA2 transgenic mice were severely decreased relative to those in wild-type littermates (Figure 5a), including IgG1, IgG2a, IgG2b and IgG3. The levels of IgG1 were decreased by about threefold, and the levels of IgG2a, IgG2b and IgG3 by 3.5-fold. In contrast, there was no difference in IgA levels. The ability of HMGA2 transgenic mice to mount an immune response to an antigen KHL was reduced by about threefold in comparison with wild-type counterparts (Figure 5b). Serum levels of IL-6 were sixfold higher and those of tumor necrosis factor alpha levels were 10-fold higher in HMGA2 transgenic animals compared with wild-type counterparts (Figure 5c).

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