Alternative titles; symbols
HGNC Approved Gene Symbol: TLX1
Cytogenetic location: 10q24.31 Genomic coordinates (GRCh38): 10:101,131,300-101,137,789 (from NCBI)
Up to 7% of childhood T-cell acute lymphoblastic leukemia (T-ALL) is accompanied by a translocation involving 10q24 as a breakpoint, either t(10;14)(q24;q11) or t(7;10)(q35;q24). The gene adjacent to the 10q24 region is transcriptionally activated after translocation to the proximity of either TCRD (see 186810) at chromosome 14q11 or TCRB (see 186930) at chromosome 7q35 (see CYTOGENETICS). Kennedy et al. (1991) cloned HOX11, a gene adjacent to the breakpoint on chromosome 10q24, from a T-ALL cell line carrying the translocation t(7;10)(q35;q24). The deduced 342-amino acid protein has an N-terminal glycine- and proline-rich domain, followed by a putative DNA-binding homeobox domain. Northern blot analysis detected a HOX11 transcript of about 2.3 kb in the T-cell line, with low expression in neuroblastoma and small cell lung carcinoma cell lines.
Dear et al. (1993) found that human HOX11 and its orthologs in other species have a threonine in helix-3 of the homeodomain rather than the more common isoleucine or valine found in other HOX proteins. Using immunofluorescence microscopy, they found that epitope-tagged human HOX11 localized to the nucleus in transfected COS cells.
Roberts et al. (1994) isolated a mouse Hox11 genomic clone and found that the homeodomain shares complete amino acid identity with human HOX11.
Kennedy et al. (1991) determined that the TLX1 gene contains at least 3 coding exons that span 7 kb. Alternative splicing may introduce a small intron into the 5-prime exon.
Greene et al. (2007) identified the TD1 gene (612734) 161 bp upstream of the TLX1 transcriptional initiation site in a head-to-head orientation. The intergenic region between TD1 and TLX1 is highly conserved between mouse and human and contains numerous GC boxes and a centrally located CCAAT box embedded within a CpG island. It has no discernible TATA box. Reporter gene assays showed that the intergenic region had robust bidirectional promoter activity for expression of both TD1 and TLX1.
The TLX1 gene maps to chromosome 10q24 (Kennedy et al., 1991). Roberts et al. (1994) mapped the mouse Hox11 gene to the syntenic region within mouse chromosome 19.
Using FISH, BAC end sequencing, and genomic database analysis, Gough et al. (2003) determined that the order of selected genes on chromosome 10q24, from centromere to telomere, is CYP2C9 (601130), PAX2 (167409), HOX11, and NFKB2 (164012).
Lu et al. (1991) found that expression of TCL3 was elevated in leukemic cells harboring the t(10;14) translocation.
Dear et al. (1993) showed that human HOX11 activated transcription of a reporter gene via a TAATGG target sequence. The homeodomain of HOX11 also bound the sequences TAAC and TAAT, suggesting that TAAC may also be a HOX11 recognition sequence.
De Keersmaecker et al. (2010) identified BCL11B (606558) mutations and deletions in 16% of human T-ALLs examined, consistent with their findings in a mouse model of TLX1-induced T-ALL (see ANIMAL MODEL). Chromatin immunoprecipitation analysis of a human T-ALL line demonstrated binding of TLX1 to the BCL11B promoter.
Kagan et al. (1987) fused human leukemic T cells carrying a t(10;14)(q24;q11) translocation with mouse leukemic T cells and examined the hybrids for genetic markers of human chromosomes 10 and 14. Hybrids containing the human 10q+ chromosome had the human genes for terminal deoxynucleotidyltransferase (TDT; 187410), which had been mapped to 10q23-q25, and for the constant region of TCR-alpha (TRAC; 186880). Hybrids containing the human 14q- chromosome retained the variable components of TCR-alpha (see 615442). Thus the 14q11 breakpoint split the TCR-alpha locus in a region between the variable and constant genes. These results suggested that the leukemic process resulted from translocation of the C(alpha) locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, with resulting deregulation of said oncogene, for which they proposed the name TCL3. Since the 10q+ chromosome retained the TDT gene, they concluded that the TDT locus is proximal to the TCL3 gene, confirming the location to band 10q23-q24.
Zutter et al. (1990) cloned the t(10;14) breakpoint from CD3-negative T-ALL cells. They identified a locus distinct from TDT at 10q24; this locus was not active in a variety of normal or other neoplastic T cells, but recognized an abundant 2.9-kb RNA in a t(10;14) T-cell leukemia. The authors speculated that this locus is a candidate for the putative TCL3 protooncogene.
Kennedy et al. (1991) identified the HOX11 gene adjacent to the breakpoint on chromosome 10q24 in T-ALL. They showed that the coding capacity of the HOX11 gene was undisturbed in a T-cell line carrying the translocation t(7;10)(q35;q24). Hatano et al. (1991) also identified the HOX11 gene adjacent to the breakpoint on 10q24 in the t(10;14) translocation of T-ALL.
Dube et al. (1991) implicated the HOX11 gene in the translocation t(10;14)(q24;q11) that occurs in T-ALL. The translocation is presumably catalyzed by recombinases normally involved in the generation of immunoglobulin and TCR diversity. Dube et al. (1991) suggested that this was the first example of a human cancer in which deregulated expression of an unaltered homeobox gene is involved in tumorigenesis.
Kleppe et al. (2010) described the identification of focal deletions of PTPN2 (176887) in human T-ALL. Deletion of PTPN2 was specifically found in T-ALLs with aberrant expression of the TLX1 transcription factor oncogene, including 4 cases also expressing the NUP214-ABL1 tyrosine kinase (114350). Knockdown of PTPN2 increased the proliferation and cytokine sensitivity of T-ALL cells. In addition, PTPN2 was identified as a negative regulator of NUP214-ABL1 kinase activity. Kleppe et al. (2010) concluded that their study provided genetic and functional evidence for a tumor suppressor role of PTPN2 and suggested that expression of PTPN2 may modulate response to treatment.
HOX11 is an orphan homeobox gene since it is located at a site outside the 4 mammalian HOX clusters. Whereas the orthodox HOX genes encode a combinatorial system of positional specification along the anterior-posterior axis of the embryo, the function of orphan homeobox genes is less well understood. As indicated by the findings in the translocation t(10;14), juxtaposition of HOX11 to the T-cell receptor gene redirects the expression of the normal HOX11 product to thymocytes. Transgenic mice in which HOX11 is redirected to the thymus develop T-cell lymphoblastic lymphoma-leukemia. To assess the functional role of Hox11 in the mouse, Roberts et al. (1994) generated Hox11-deficient mice through gene targeting. Homozygous deficient mice had no spleen, but otherwise appeared normal. Hox11 is normally expressed in the splanchnic anlage arising from the splanchnic mesoderm. The homozygous deficient embryos had no cellular organization at the site of the splanchnic development, but all other splanchnic derivatives developed normally. Roberts et al. (1994) concluded that Hox11 controls the genesis of a single organ; their finding provided new insight into the genetic regulation of morphogenesis.
Dear et al. (1995) performed similar studies in 'knockout' mice and found that, in homozygous Hox11-null embryos, spleen formation commences normally up to a specific stage of embryogenesis, at which point the spleen anlage undergoes rapid and complete resorption. Dying spleen cells exhibited characteristics of apoptosis. The authors concluded that Hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis.
Wellik and Capecchi (2003) generated mice in which all members of the Hox10 (142993) and/or Hox11 paralogous group are disrupted and showed that these genes are global regulators of the lumbosacral region of the axial skeleton and are integral in patterning principal limb elements. In the absence of Hox10 function, no lumbar vertebrae are formed. Instead, ribs project from all posterior vertebrae, extending caudally from the last thoracic vertebrae to beyond the sacral region. In the absence of Hox11 function, sacral vertebrae are not formed and instead these vertebrae assume a lumbar identity. The redundancy among these paralogous family members is so great that this global aspect of Hox patterning is not apparent in mice that are mutant for 5 of the 6 paralogous alleles.
Using Tlx3 (604640)-null, Tlx1-null, and compound Tlx1/3-null mice, Cheng et al. (2004) found that Tlx3 and Tlx1 act as selector genes to promote excitatory glutamatergic over inhibitory GABAergic differentiation in the superficial laminar neurons of the spinal dorsal horn. In developing chick spinal cord (embryonic day 5), ectopic Tlx3 expression was sufficient to repress endogenous GABAergic differentiation and induce formation of glutamatergic cells, thereby changing cell fate. Cheng et al. (2004) suggested that the defects in central respiratory control in Tlx3-deficient mice may be a result of excess inhibitory GABAergic synaptic input. The authors noted that Tlx1 and Tlx3 are not expressed in the mouse forebrain, suggesting that glutamatergic and GABAergic transmitter phenotypes are regulated by region-specific genes in the central nervous system.
Using mice with conditional transgenic expression of human TLX1 in T-cell progenitors, De Keersmaecker et al. (2010) generated a mouse model of TLX1-induced T-ALL. Array comparative genomic hybridization and sequence analysis identified mutations in Notch1 (190198) and, in nearly half of mouse TLX1-induced tumors, mutations or deletions in Bcl11b. Spectral karyotype, array comparative genomic hybridization, and microarray analysis showed evidence of aneuploidy in mouse TLX1-induced tumors and downregulation of Chek1 (603078) and other mitotic control genes. De Keersmaecker et al. (2010) concluded that TLX1 translocation induces loss of the mitotic checkpoint in nontransformed proleukemic thymocytes, chromosomal missegregation, and aneuploidy in the earliest stages of tumor development.
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Lu, M., Gong, Z. Y., Shen, W. F., Ho, A. D. The TCL-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein. EMBO J. 10: 2905-2910, 1991. [PubMed: 1717256] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07840.x]
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Wellik, D. M., Capecchi, M. R. Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science 301: 363-367, 2003. [PubMed: 12869760] [Full Text: https://doi.org/10.1126/science.1085672]
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