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

Konstantin Krutikov,Yanzhen Zheng,Margaret R Hough,Xiaoyong Huang,Andrea K Vaags,Alden Chesney,Valentina Evdokimova,Edwin Chen,Arun Rishi

doi:10.1371/journal.pone.0089649

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-TLX1Tg 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-TLX1Tg mice with mice deficient in the DNA repair enzyme DNA-PK (PrkdcScid/Scid mice). IgHµ-TLX1TgPrkdcScid/Scid mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control PrkdcScid/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-TLX1TgPrkdcScid/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.

Highlights

The homeobox gene TLX1 encodes a member of the nonclustered subclass of homeodomain-containing transcription factors
To determine whether dysregulation of a DNA repair pathway collaborated with ectopic expression of TLX1 in disease progression, we crossed IgHm-TLX1Tg mice with CB17 ICR-Prkdcscid mice
The first transgenic mouse model confirming the oncogenic potential of TLX1 in vivo was reported by Hough et al [11]

Summary

Introduction

The homeobox gene TLX1 encodes a member of the nonclustered subclass of homeodomain-containing transcription factors. TLX1 was initially identified at the breakpoint of the t(10;14)(q24;q11) reciprocal chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL) [1,2,3]. This translocation places the entire TLX1 coding region under the transcriptional control of the T cell receptor d (TCRd) promoter resulting in inappropriate expression of TLX1 in T cells, and is found in ,5% of pediatric T-ALL and 30% of adult T-ALL cases. TLX1 is not typically expressed in adult tissues but is critical for the development of the spleen during embryogenesis [8,9,10]

Methods

Results

Conclusion