Molecular Pathways TLX1-Induced T-cell Acute Lymphoblastic Leukemia Kim De Keersmaecker 1,2 and Adolfo A. Ferrando 3,4,5 Abstract The TLX1 transcription factor oncogene is frequently activated by chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL) and defines a distinct molecular group of tumors characterized by differentiation arrest at the early cortical stage of thymocyte differentiation and excellent response to therapy. Recent developments from the analysis of genomic data on TLX1-specific transcriptional targets and analysis of the molecular mechanisms of TLX1 transformation in human- and mouse-induced leukemias have shown novel insight into the activity of this transcription factor oncogene. Aberrant expression of TLX1 in T-cell progenitors disrupts normal T-cell development and triggers the development of aneuploidy during T-cell transformation. Importantly, the disruption of the mitotic checkpoint in TLX1-induced tumors may be linked not only to the acquisition of secondary genetic alterations in T-ALL but also to increased sensitivity of these tumors to chemotherapy with drugs targeting the formation of the mitotic spindle. Clin Cancer Res; 17(20); 6381–6. Ó2011 AACR. Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggres- sive hematologic cancer caused by malignant transforma- tion of developing T cells. The TLX1 transcription factor oncogene is the target of translocation t(10;14)(q24;q11) in 5% to 10% of pediatric and up to 30% of adult T-ALL cases (1–4). This translocation juxtaposes an intact TLX1 gene to the very strong enhancer elements of the T-cell receptor loci, resulting in aberrantly high TLX1 expression levels. TLX1 (also known as HOX11) is the founding member of a family of orphan HOX genes, encoded in loci located outside the A, B, C, and D paralog groups. In addition to TLX1, the TLX family of transcription regulators includes TLX2 and TLX3 (5) and is characterized by the presence of a threonine in the third helix of the homeodomain, which confers specific DNA-binding properties. Like other HOX genes, TLX factors play important roles during develop- ment. Under normal conditions, TLX1 expression is only detected during embryonic life in the mouse and is restricted to the branchial arches, the hindbrain, and the splenic primordium (6, 7). Moreover, TLX1 plays a critical role for spleen development, and Tlx1 knockout mice show complete agenesis of the spleen in the absence of other developmental alterations (8, 9). Among T-ALL patients, TLX1-expressing tumors consti- tute a distinct molecular group, characterized by a block in T-cell differentiation at the early cortical stage of T-cell development (2) and by a favorable prognosis (1, 2, 10). Moreover, TLX1-induced leukemias represent a dis- tinct oncogenic group with specific genetic alterations rarely found in non–TLX-induced T-ALLs, including the rearrangement of the NUP214-ABL1 oncogene (11), dele- tion of the PTPN2 phosphatase (12), and mutations in the WT1 (13) and PHF6 (14) tumor suppressor genes. How- ever, until recently, very little was known about the specific mechanisms that mediate T-cell transformation down- stream of TLX1. Moreover, the generation of a mouse model of TLX1-induced T-ALL eluded the efforts of several groups over the past decade (15, 16). In this context, the generation of an LCK-TLX1 transgenic mouse model that recapitulates the histologic, transcriptional, and genetic features of TLX1-induced T-ALL has provided a much- needed tool for the analysis of the molecular and cellular mechanisms of TLX1-induced transformation (16). In these studies, LCK-TLX1 transgenic mice showed acceler- ated mortality owing to the development of clonal T-ALL tumors, occurring with an average latency of 6 months and a penetrance of more than 90% (16). Notably, almost identical phenotypes were observed in 3 different founder lines, ruling out a role for insertional mutations introduced during the generation of the transgene in the oncogenic process. TLX1-induced mouse leukemias showed clonal rearrangements of the TCRB locus (16) and were trans- plantable, although with a low leukemia-initiating cell content (A.A. Ferrando and K. De Keersmaeker, unpub- lished results). Mouse models of cancer have been instrumental in the analysis of genetic interactions between oncogenes and tumor suppressors and are increasingly being recognized as invaluable tools for the analysis of the basic mechanisms Authors' Affiliations: 1 Department of Molecular and Developmental Genetics, VIB, 2 Center for Human Genetics, KU Leuven, Leuven, Belgium; Departments of 3 Pediatrics and 4 Pathology, and 5 Institute for Cancer Genetics, Columbia University, New York, New York Corresponding Author: Adolfo A. Ferrando, Columbia University Medical Center, 1130 St. Nicholas Avenue, ICRC 402A, New York, NY, 10032. Phone: 212-851-4611; Fax: 212-851-5256; E-mail: af2196@columbia.edu doi: 10.1158/1078-0432.CCR-10-3037 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 6381 on May 9, 2017. © 2011 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from Published OnlineFirst June 24, 2011; DOI: 10.1158/1078-0432.CCR-10-3037