Ectopic TLX1 Expression Accelerates Malignancies in Mice Deficient in DNA-PK

摘要: The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This results inappropriate expression TLX1 cells. oncogenic potential was demonstrated IgHμ-TLX1Tg mice which develop mature B lymphoma after a long latency period, suggesting requirement additional mutations to initiate malignancy. To determine whether dysregulation genes involved DNA damage response contributed tumor progression, we crossed deficient repair enzyme DNA-PK (PrkdcScid/Scid mice). IgHµ-TLX1TgPrkdcScid/Scid developed T-ALL and myeloid (AML) reduced relative control PrkdcScid/Scid mice. Further analysis thymi from premalignant revealed greater thymic cellularity concomitant increased thymocyte proliferation decreased apoptotic index. Moreover, malignant thymocytes exhibited impaired spindle checkpoint function, association aneuploid karyotypes. Gene profiling dysregulated cycle, mitotic double negative 2 (DN2) DN3 stage thymocytes. Collectively, these findings reveal novel synergy between pathway leukemogenesis.