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T-CELL LEUKEMIA HOMEOBOX 3; TLX3

T-CELL LEUKEMIA HOMEOBOX 3; TLX3

Alternative titles; symbolsHOMEOBOX 11-LIKE 2; HOX11L2RESPIRATORY NEURON HOMEOBOX, MOUSE, HOMOLOG OF; RNXHGNC Approved Gene Symbol: TLX3Cytogenetic location: 5q3...

Alternative titles; symbols

  • HOMEOBOX 11-LIKE 2; HOX11L2
  • RESPIRATORY NEURON HOMEOBOX, MOUSE, HOMOLOG OF; RNX

HGNC Approved Gene Symbol: TLX3

Cytogenetic location: 5q35.1 Genomic coordinates (GRCh38): 5:171,309,247-171,312,138 (from NCBI)

▼ Description
RNX (HOX11L2, TLX3) belongs to a family of orphan homeobox genes that encode DNA-binding nuclear transcription factors. Members of the HOX11 gene family are characterized by a threonine-47 replacing cytosine in the highly conserved homeodomain (Dear et al., 1993).

▼ Gene Function
In situ hybridization studies by Shirasawa et al. (2000) in mice revealed considerable overlap of 3 Hox11 genes, Rnx, Tlx1 (186770) and Tlx2 (604240), in their expression within the nervous system, but Rnx was singularly expressed in the developing dorsal and ventral region of the medulla oblongata. Tlx1-deficient and Tlx2-deficient mice displayed phenotypes in tissues where the mutated gene was singularly expressed, resulting in asplenogenesis and hyperganglionic megacolon, respectively. To determine the developmental role of Rnx in the mouse, Shirasawa et al. (2000) disrupted the locus in mouse embryonic stem (ES) cells. Rnx-deficient mice developed to term, but all died within 24 hours after birth from a central respiratory failure. The electromyographic activity of intercostal muscles coupled with the C4 ventral root activity assessed in a medulla-spinal cord preparation revealed a high respiratory rate with short inspiratory duration and frequent apnea. Furthermore, a coordinate pattern existed between the abnormal activity of inspiratory neurons in the ventrolateral medulla and C4 motor neuron output, indicating a central respiratory defect in Rnx -/- mice. Thus, Rnx is critical for the development of the ventral medullary respiratory center.

Using Tlx3 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.

Role in Leukemia

Bernard et al. (2001) used fluorescence in situ hybridization to characterize a cryptic translocation, t(5;14)(q35;q32), in T-cell acute lymphoblastic leukemia (T-ALL). The translocation was present in 5 of 23 (22%) children and adolescents with T-ALL tested. RANBP17 (606141), a gene coding for a member of the importin-beta protein family, and HOX11L2 were mapped close to the chromosome 5 breakpoints, and CTIP2 (606558), which is highly expressed during normal T-cell differentiation, was localized in the vicinity of the chromosome 14 breakpoints. The HOX11L2 gene was found to be transcriptionally activated as a result of the translocation, probably under the influence of CTIP2 transcriptional regulation elements. These data established t(5;14)(q35;q32) as a major abnormality, and HOX11 family member activation as an important pathway in T-ALL leukemogenesis.

Human T-cell leukemias can arise from activation of oncogenes by specific chromosomal translocations involving the T-cell receptor genes. Ferrando et al. (2002) showed that 5 different T-cell oncogenes--HOX11, TAL1 (187040), LMO1 (186921), LMO2 (180385), and LYL1 (151440)--are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, they identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development. Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T-cell leukemogenesis. HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or HOX11L2 confers a much worse response to treatment.

Ballerini et al. (2002) analyzed 28 samples from childhood T-ALL and found expression of HOX11L2 in 6 patients and of HOX11 in 3 patients. With 1 exception, these activations did not occur simultaneously in the same patients, and allowed the subclassification of 50% of the patients. In 1 instance each, HOX11L1 and HOX11 expression was observed in the absence of detectable chromosomal abnormality of their respective loci.

▼ Mapping
By radiation hybrid analysis, Lee-Kirsch et al. (2001) mapped the HOX11L2 gene to chromosome 5q34-q35. By FISH and radiation hybrid analysis, Cinti et al. (2001) mapped the gene to chromosome 5q35.1, flanked by markers D5S625 and D5S429. By FISH, they mapped the mouse counterpart to chromosome 11A4-A5.

▼ Molecular Genetics
Exclusion Studies

Shirasawa et al. (2000) found that deficiency of Rnx in mice results in a syndrome resembling congenital central hypoventilation (CCHS; see 209880). However, screening of the RNX gene in a series of 25 patients with CCHS revealed no nucleotide variation that could be related to the disorder (Amiel et al., 2003).

Tags: 5q35.1