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Ectopic TLX1 expression accelerates malignancies in mice deficient in DNA-PK.

Krutikov K, Zheng Y, Chesney A, Huang X, Vaags AK, Evdokimova V, Hough MR, Chen E - PLoS ONE (2014)

Bottom Line: This translocation results in the inappropriate expression of TLX1 in T cells.Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index.Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.

ABSTRACT
The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1(Tg) mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1(Tg) mice with mice deficient in the DNA repair enzyme DNA-PK (Prkdc(Scid/Scid) mice). IgHµ-TLX1(Tg)Prkdc(Scid/Scid) mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control Prkdc(Scid/Scid) mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1(Tg)Prkdc(Scid/Scid) thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2) and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

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TLX1-induced T-ALL in IgHµ-TLX1TgPrkdcScid/Scid mice.(A) Hematoxylin and eosin staining of tissues isolated from premalignant PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice and IgHµ-TLX1TgPrkdcScid/Scid mice diagnosed with T-ALL. Magnification x40 (overview) and x100 (insert). Scale bars, 10 µm. (B) Immunohistochemical analysis of thymus and spleen from a premalignant IgHµ-TLX1TgPrkdcScid/Scid mouse and a moribund IgHµ-TLX1TgPrkdcScid/Scid mouse stained with an anti-Thy1.2 antibody. Magnification x20. Scale bars, 10 µm. (C) Cells from thymi, spleens and bone marrow of premalignant and moribund IgHµ-TLX1TgPrkdcScid/Scid mice were examined for cell surface expression of CD44, CD25, CD4, CD8, CD3, TCRαβ, TCRγδ and Thy1.2 (for T cells) and Gr-1 and Mac-1 (for myeloid cells).
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pone-0089649-g003: TLX1-induced T-ALL in IgHµ-TLX1TgPrkdcScid/Scid mice.(A) Hematoxylin and eosin staining of tissues isolated from premalignant PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice and IgHµ-TLX1TgPrkdcScid/Scid mice diagnosed with T-ALL. Magnification x40 (overview) and x100 (insert). Scale bars, 10 µm. (B) Immunohistochemical analysis of thymus and spleen from a premalignant IgHµ-TLX1TgPrkdcScid/Scid mouse and a moribund IgHµ-TLX1TgPrkdcScid/Scid mouse stained with an anti-Thy1.2 antibody. Magnification x20. Scale bars, 10 µm. (C) Cells from thymi, spleens and bone marrow of premalignant and moribund IgHµ-TLX1TgPrkdcScid/Scid mice were examined for cell surface expression of CD44, CD25, CD4, CD8, CD3, TCRαβ, TCRγδ and Thy1.2 (for T cells) and Gr-1 and Mac-1 (for myeloid cells).

Mentions: In total, 59% of IgHμ-TLX1TgPrkdcScid/Scid mice and 54% of PrkdcScid/Scid mice developed an immature T-cell leukemia. The median survival of IgHμ-TLX1TgPrkdcScid/Scid mice with T-ALL was 6.5 months, whereas PrkdcScid/Scid mice exhibited a protracted latency with a median survival of 8.25 months (Figure 2B, D). Histological examination of tissues of PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice exhibiting T-ALL indicated thymic involvement in 100% of animals, while splenic and bone marrow infiltration of tumor cells was detected in 67% and 52% of mice, respectively. This suggests that the thymus was the primary site for disease initiation. The architecture of the thymus was disrupted with indistinguishable cortico-medullary delineation. The spleens had disrupted follicles, with patchy areas infiltrated with a large, relatively uniform population of lymphocytes having polylobulated pleomorphic nuclei with diffuse, loose, speckled, open chromatin and prominent nucleoli (Figure 3A).


Ectopic TLX1 expression accelerates malignancies in mice deficient in DNA-PK.

Krutikov K, Zheng Y, Chesney A, Huang X, Vaags AK, Evdokimova V, Hough MR, Chen E - PLoS ONE (2014)

TLX1-induced T-ALL in IgHµ-TLX1TgPrkdcScid/Scid mice.(A) Hematoxylin and eosin staining of tissues isolated from premalignant PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice and IgHµ-TLX1TgPrkdcScid/Scid mice diagnosed with T-ALL. Magnification x40 (overview) and x100 (insert). Scale bars, 10 µm. (B) Immunohistochemical analysis of thymus and spleen from a premalignant IgHµ-TLX1TgPrkdcScid/Scid mouse and a moribund IgHµ-TLX1TgPrkdcScid/Scid mouse stained with an anti-Thy1.2 antibody. Magnification x20. Scale bars, 10 µm. (C) Cells from thymi, spleens and bone marrow of premalignant and moribund IgHµ-TLX1TgPrkdcScid/Scid mice were examined for cell surface expression of CD44, CD25, CD4, CD8, CD3, TCRαβ, TCRγδ and Thy1.2 (for T cells) and Gr-1 and Mac-1 (for myeloid cells).
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pone-0089649-g003: TLX1-induced T-ALL in IgHµ-TLX1TgPrkdcScid/Scid mice.(A) Hematoxylin and eosin staining of tissues isolated from premalignant PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice and IgHµ-TLX1TgPrkdcScid/Scid mice diagnosed with T-ALL. Magnification x40 (overview) and x100 (insert). Scale bars, 10 µm. (B) Immunohistochemical analysis of thymus and spleen from a premalignant IgHµ-TLX1TgPrkdcScid/Scid mouse and a moribund IgHµ-TLX1TgPrkdcScid/Scid mouse stained with an anti-Thy1.2 antibody. Magnification x20. Scale bars, 10 µm. (C) Cells from thymi, spleens and bone marrow of premalignant and moribund IgHµ-TLX1TgPrkdcScid/Scid mice were examined for cell surface expression of CD44, CD25, CD4, CD8, CD3, TCRαβ, TCRγδ and Thy1.2 (for T cells) and Gr-1 and Mac-1 (for myeloid cells).
Mentions: In total, 59% of IgHμ-TLX1TgPrkdcScid/Scid mice and 54% of PrkdcScid/Scid mice developed an immature T-cell leukemia. The median survival of IgHμ-TLX1TgPrkdcScid/Scid mice with T-ALL was 6.5 months, whereas PrkdcScid/Scid mice exhibited a protracted latency with a median survival of 8.25 months (Figure 2B, D). Histological examination of tissues of PrkdcScid/Scid and IgHµ-TLX1TgPrkdcScid/Scid mice exhibiting T-ALL indicated thymic involvement in 100% of animals, while splenic and bone marrow infiltration of tumor cells was detected in 67% and 52% of mice, respectively. This suggests that the thymus was the primary site for disease initiation. The architecture of the thymus was disrupted with indistinguishable cortico-medullary delineation. The spleens had disrupted follicles, with patchy areas infiltrated with a large, relatively uniform population of lymphocytes having polylobulated pleomorphic nuclei with diffuse, loose, speckled, open chromatin and prominent nucleoli (Figure 3A).

Bottom Line: This translocation results in the inappropriate expression of TLX1 in T cells.Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index.Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada ; Department of Molecular and Cellular Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.

ABSTRACT
The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1(Tg) mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1(Tg) mice with mice deficient in the DNA repair enzyme DNA-PK (Prkdc(Scid/Scid) mice). IgHµ-TLX1(Tg)Prkdc(Scid/Scid) mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control Prkdc(Scid/Scid) mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1(Tg)Prkdc(Scid/Scid) thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2) and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis.

Show MeSH
Related in: MedlinePlus