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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) Proliferation of malignant T cells from Eμ-HMGA2 transgenic mice and normal T cells from wild-type control animals. The numbers indicate the frequency of CD4+ population. Representative images for five mice per genotype. (b) Proliferation rate of transgenic and wild type splenocytes.
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fig4: (a) Proliferation of malignant T cells from Eμ-HMGA2 transgenic mice and normal T cells from wild-type control animals. The numbers indicate the frequency of CD4+ population. Representative images for five mice per genotype. (b) Proliferation rate of transgenic and wild type splenocytes.

Mentions: The T-ALL neoplastic cells are actively proliferating.17 The majority (67±9.4%, n=5) of splenic T cells from HMGA2 transgenic animals but essentially no cells (1.05±0.19%, n=5, P<0.0001) from age-matched wild-type mice exhibited substantial BrdU incorporation (Figures 4a and b), showing that T cells in the transgenic mice were proliferating robustly.


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) Proliferation of malignant T cells from Eμ-HMGA2 transgenic mice and normal T cells from wild-type control animals. The numbers indicate the frequency of CD4+ population. Representative images for five mice per genotype. (b) Proliferation rate of transgenic and wild type splenocytes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: (a) Proliferation of malignant T cells from Eμ-HMGA2 transgenic mice and normal T cells from wild-type control animals. The numbers indicate the frequency of CD4+ population. Representative images for five mice per genotype. (b) Proliferation rate of transgenic and wild type splenocytes.
Mentions: The T-ALL neoplastic cells are actively proliferating.17 The majority (67±9.4%, n=5) of splenic T cells from HMGA2 transgenic animals but essentially no cells (1.05±0.19%, n=5, P<0.0001) from age-matched wild-type mice exhibited substantial BrdU incorporation (Figures 4a and b), showing that T cells in the transgenic mice were proliferating robustly.

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