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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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Immunophenotype of TLX1-induced T-ALL.Immunophenotype distribution showing heterogeneous expression of CD44, CD25, CD4 and CD8 in IgHµ-TLX1TgPrkdcScid/Scid T-ALL. Representative flow diagrams showing heterogeneous expression of CD4 and CD8 in TLX1-initiated leukemia are presented.
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pone-0089649-g004: Immunophenotype of TLX1-induced T-ALL.Immunophenotype distribution showing heterogeneous expression of CD44, CD25, CD4 and CD8 in IgHµ-TLX1TgPrkdcScid/Scid T-ALL. Representative flow diagrams showing heterogeneous expression of CD4 and CD8 in TLX1-initiated leukemia are presented.

Mentions: Flow cytometric analysis revealed heterogeneity in the tumor phenotype with respect to expression of CD4 and CD8 (Figure 3C) with tumor cells isolated from the thymus, spleen and bone marrow expressing both CD4 and CD8 or only CD4 with decreased levels of expression of CD44 and CD25. Other tumors consisted of CD44 and CD25 expressing cells with profiles typical of DN1, DN2 and DN3 cells or only DN3 thymocytes. Tumor cells did not expressed αβ- or γδ- T cell receptors, indicative of an immature thymocyte phenotype (Figure 3C). The majority (60%) of thymic tumors had a mixed phenotype expressing low-levels of CD4 and CD8 along with a combination of CD44 and CD25 (Figure 4).


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)

Immunophenotype of TLX1-induced T-ALL.Immunophenotype distribution showing heterogeneous expression of CD44, CD25, CD4 and CD8 in IgHµ-TLX1TgPrkdcScid/Scid T-ALL. Representative flow diagrams showing heterogeneous expression of CD4 and CD8 in TLX1-initiated leukemia are presented.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935916&req=5

pone-0089649-g004: Immunophenotype of TLX1-induced T-ALL.Immunophenotype distribution showing heterogeneous expression of CD44, CD25, CD4 and CD8 in IgHµ-TLX1TgPrkdcScid/Scid T-ALL. Representative flow diagrams showing heterogeneous expression of CD4 and CD8 in TLX1-initiated leukemia are presented.
Mentions: Flow cytometric analysis revealed heterogeneity in the tumor phenotype with respect to expression of CD4 and CD8 (Figure 3C) with tumor cells isolated from the thymus, spleen and bone marrow expressing both CD4 and CD8 or only CD4 with decreased levels of expression of CD44 and CD25. Other tumors consisted of CD44 and CD25 expressing cells with profiles typical of DN1, DN2 and DN3 cells or only DN3 thymocytes. Tumor cells did not expressed αβ- or γδ- T cell receptors, indicative of an immature thymocyte phenotype (Figure 3C). The majority (60%) of thymic tumors had a mixed phenotype expressing low-levels of CD4 and CD8 along with a combination of CD44 and CD25 (Figure 4).

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