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Transcription Factor Encyclopedia  BETA
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TLX1 (previously known as HOX11 orTCL3) is an orphan homeobox gene. It was originally discovered in association with 4-7% of cases of T cell acute lymphoblastic leukemias harbouring a t(10;14)(q24;q11) cytogenetic abnormality. Studies by three independent groups discovered the presence of the TLX1 gene on chromosome 10q24 juxtaposed with the T cell receptor (TCR) delta regulatory elements on chromosome 10, resulting in aberrant over-expression of the full and intact TLX1 gene[1][2][3]. Juxtaposition with the TCR alpha locus was also seen [2]. Elevated TLX1 expression in leukemic blasts in also detected in the absence of a translocation in ~50% (37/76) of pediatric T-ALL cases[4], as well as rare cases of B-ALL[5]. Clinically, TLX1+ T-ALLs are associated with a genetic signature associated with maturation arrest at an early cortical thymocyte stage of T cell development[6], and respond well to conventional chemotherapy[7].

The TLX1 gene encodes a 342-amino acid protein with a N-terminal glycine- and proline-rich domain, followed by a putative DNA-binding homeodomain. TLX1 is the founding member of the TLX family of homeobox genes (which also includes TLX2 and TLX3), which is distinguished by a threonine in helix-3 of the homeodomain rather than the more common isoleucine or valine found in other HOX proteins[8]. Like most homeobox genes, the canonical role of TLX1 appears to be in spleen development. Tlx1-knockout mice are asplenic[9] and exhibit a mildly delayed cytotoxic response to vaccinia virus infection[10], but are otherwise developmentally normal. Chimeric studies revealed a critical role for TLX1 in directing mesodermal precursors down a splenic cell fate during embryogenesis[11].

The molecular role of TLX1 in mediating cellular transformation, however, remains unclear and is the subject of active investigation. To date, it is recognized that there are both transcription dependent and independent mechanisms of TLX1-induced oncogenesis which may not be mutually exclusive. The transcription-dependent mechanisms implicate target genes transactivated by TLX1:PBX1 heterodimers as being important for eliciting cellular transformation [12]. However, to date, the actual genes targeted by TLX1 in association with leukemogenesis remain unclear. Several studies have also indicated that TLX1 may promote oncogenesis through roles independent of direct transcriptional activation of target genes. Rather, TLX1 has been proposed to exert its leukemogenic effects through discruption of multiple cell cycle processes, mediated largely through direct protein-protein interaction with key players of the cell cycle apparatus at multiple cell cycle checkpoints. In particular, it has been shown to bind directly with the protein phosphatases PP1 and PP2A, which has been implicated in aberrant G1/S, G2/M and spindle checkpoint transition [13][14].

  1. Dubé ID et al. A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10;14). Blood, 78(11):2996-3003. (PMID 1683261)
  2. Kennedy MA et al. HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24. Proc. Natl. Acad. Sci. U.S.A., 88(20):8900-4. (PMID 1681546)
  3. Hatano M et al. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science, 253(5015):79-82. (PMID 1676542)
  4. Kees UR et al. Expression of HOX11 in childhood T-lineage acute lymphoblastic leukaemia can occur in the absence of cytogenetic aberration at 10q24: a study from the Children's Cancer Group (CCG). Leukemia, 17(5):887-93. (PMID 12750702)
  5. He J et al. [Detection of fusion genes resulting from chromosome abnormalities in childhood acute lymphoblastic leukemia] Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 22(5):551-3. (PMID 16215946)
  6. Ferrando AA and Look AT. Gene expression profiling in T-cell acute lymphoblastic leukemia. Semin. Hematol., 40(4):274-80. (PMID 14582078)
  7. Bergeron J et al. Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs. Blood, 110(7):2324-30. (PMID 17609427)
  1. Dear TN et al. The HOX11 gene encodes a DNA-binding nuclear transcription factor belonging to a distinct family of homeobox genes. Proc. Natl. Acad. Sci. U.S.A., 90(10):4431-5. (PMID 8099440)
  2. Roberts CW et al. Hox11 controls the genesis of the spleen. Nature, 368(6473):747-9. (PMID 7908720)
  3. Karrer U et al. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/-) mutant mice. J. Exp. Med., 185(12):2157-70. (PMID 9182687)
  4. Dear TN et al. The Hox11 gene is essential for cell survival during spleen development. Development, 121(9):2909-15. (PMID 7555717)
  5. Owens BM et al. Specific homeodomain-DNA interactions are required for HOX11-mediated transformation. Blood, 101(12):4966-74. (PMID 12586625)
  6. Kawabe T et al. HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. Nature, 385(6615):454-8. (PMID 9009195)
  7. Riz I and Hawley RG. G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia. Oncogene, 24(36):5561-75. (PMID 15897879)
FIGURE 1 TLX1 Activation in T-cell Acute Lymphoblastic Leukemia
Juxtaposition of the TLX1 gene on chromosome 10q24 with the TCRdelta regulatory elements on chromosome 14q11 is seen in approximately 5-7% of T-cell acute lymphoblastic leukemias. The reciprocol translocation results in aberrant overexpression of the intact TLX1 gene in T cells.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.