Disease relevance of TLX1

• The TLX1/HOX11 homeobox gene was originally identified at the recurrent t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T-cell acute lymphoblastic leukemias (T-ALLs) [1].
• A translocation involving human chromosome 10, band q24, in a subset of T-cell acute leukemias disrupts a region surrounding the putative oncogene HOX11, which encodes a protein with a homeodomain [2].
• The majority of patients with HOX11 T-ALL underwent allografting, predominantly in second CR, but were not associated with a superior OS [3].
• HOX11L1 and HOX11 expression were observed in one instance each, in the absence of detectable chromosomal abnormality of their respective loci, on chromosomes 2 and 10, respectively [4].
• These data indicate that HOX11 lymphoma cells express tumor-rejection antigens that are recognized as foreign in healthy transgenic mice and that lymphomagenesis is associated with the induction of anergy to tumor antigen-specific T cells [5].

High impact information on TLX1

• G2 arrest can be induced by gamma-irradiation, but is eliminated by expression of HOX11 within a T-cell line [6].
• Hox11 is an orphan homeobox gene that controls the genesis of the spleen [6].
• Transgenic mice that redirected HOX11 to the thymus demonstrated cell-cycle aberration and progression to malignancy [6].
• We observed that the protein HOX11 interacted with protein serine-threonine phosphatase 2A catalytic subunit (PP2AC), as well as protein phosphatase 1 (PP1C) in mammalian cells [6].
• Molecular cloning of the t(10;14)(q24;q11) recurrent breakpoint of T cell acute lymphoblastic leukemia has demonstrated a transcript for the candidate gene TCL3 [7].

Chemical compound and disease context of TLX1

• To better understand the pathogenetic role of HOX11 in leukemogenesis, post 5-fluorouracil-treated murine bone marrow cells were infected with a replication-defective retrovirus bearing the gene [8].

Biological context of TLX1

• Only the TLX1 oncogene expression subgroup showed difference in leukaemia-specific survival [9].
• Based on these findings, we identify a synergistic role between TLX1/HOX11 overexpression and Ubr1 inactivation in promoting chromosome missegregation, permitting the accrual of additional chromosome losses and cytogenic abnormalities en route to malignancy.Oncogene (2006) 25, 5752-5763. doi:10.1038/sj.onc.1209573; published online 24 July 2006 [1].
• Loss of Ubr1 promotes aneuploidy and accelerates B-cell lymphomagenesis in TLX1/HOX11-transgenic mice [1].
• Using a whole-genome PCR approach, we show here that TLX1 protein directly interacts with pericentromeric human satellite 2 DNA sequences [10].
• The interaction was confirmed in vitro and in vivo by gel retardation and chromatin immunoprecipitation assays involving satellite 2 DNA, which contained sequences resembling TLX1 binding sites [10].

Anatomical context of TLX1

• Our results suggest that overexpression of TLX1 confers a good outlook for adults with T-cell acute lymphoblastic leukaemia [9].
• Furthermore, our findings lead to questions about whether stem-cell transplantation in first remission is necessary for effective treatment of patients in the low-risk subgroup of patients with TLX1 oncogene expression [9].
• Microinjection of HOX11 into Xenopus oocytes arrested at the G2 phase of the cell cycle promoted progression to the M phase [6].
• The HOX11 protein binds to a specific DNA sequence, it localizes to the cell nucleus, and it transactivates transcription of a reporter gene linked to a cis-regulatory element, suggesting that HOX11 functions in vivo as a positive transcription activator [2].
• Here, we employed oligonucleotide microarrays to compare the expression profiles of the K3P and Sil leukemic cell lines originating from patients with HOX11+ T-ALL to that of Jurkat cells, which originated from a distinct subtype of T-ALL (TAL1+) [11].

Associations of TLX1 with chemical compounds

• The gene encoding the retinoic acid-synthesizing enzyme aldehyde dehydrogenase 1 (Aldh1), initially called Hdg-1, was found to be ectopically activated by HOX11 in this system [12].
• The HOX-11 gene expression was also suppressed by the tyrosine kinase inhibitors tryphostin and lavendustin A [13].
• In the presence of cycloheximide, a protein synthesis inhibitor, phytohemagglutinin-induced HOX-11 up-regulation was suppressed, indicating that HOX-11 acts as a delayed early response gene which requires protein synthesis [13].

Physical interactions of TLX1

• First, a PBX2 Regulatory Element PRE-1048 has been identified which contains a novel DNA-binding sequence and mediates significant activation of the HOX11 gene in K562 cells [14].
• The HOX11 gene encodes a DNA-binding nuclear transcription factor belonging to a distinct family of homeobox genes [2].
• HOX11 was shown to interact in vitro and in vivo with CTF1 [15].

Regulatory relationships of TLX1

• The T-cell oncogenic protein HOX11 activates Aldh1 expression in NIH 3T3 cells but represses its expression in mouse spleen development [12].
• The results support the hypothesis that the transforming capacity of HOX11 derives from its ability to alter the expression of genes regulating hematopoietic differentiation and that secondary mutations promoting cell survival or stimulating proliferation are required for progression to malignancy [8].

Other interactions of TLX1

• Inclusion of HOXA-translocated cases in a general molecular portrait of 92 T-ALLs based on large-scale expression analysis shows that this rearrangement defines a new homogeneous subgroup, which shares common biologic networks with the TLX1- and TLX3-related cases [16].
• Additionally, in 138 of these patients, HOX11 expression and SIL-TAL rearrangement were also assessed [17].
• SIL-TAL1 fusion was detected in association with HOX11 expression in one patient and with a t(8;14) (q24;q11) in another [4].
• The chromosomal translocations involving LMO2 (t(11;14)(p13;q11)), Ttg-1 (t(11;14)(p15;q11)), and Hox11 (t(10;14)(q24;q11)) are among the clearest examples in which it appears that a D or J segment has synapsed with an adventitious heptamer/nonamer at a gene outside of one of the antigen receptor loci [18].
• Patients with HOX11-positive lymphoblasts have an excellent prognosis when treated with modern combination chemotherapy, while cases at high risk of early failure are included largely in the TAL1- and LYL1-positive groups [19].

Analytical, diagnostic and therapeutic context of TLX1

• Using immunofluorescence microscopy, TLX1 demonstrated a punctate pattern of staining in the nuclei of leukemic T-cells (ALL-SIL) [10].
• By using oligonucleotide primers flanking an intron of the HOX-11 gene, we have developed a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for the expression of HOX-11 [20].
• Sequence analysis of the translocation breakpoint junctions on the der(14q-) chromosome in six patients carrying a t(10;14) chromosome translocation revealed that the breakpoint occurred 5' to the HOX11 protooncogene at the breakpoint cluster region [21].
• None of 53 B-lineage ALLs was positive for HOX11 expression, however, Northern blot and RT-PCR analysis revealed that four of 12 T-ALLs (33%) showed expression of the gene [22].
• Detection of translocations involving the HOX11/TCL3-locus in 10q24 by interphase fluorescence in situ hybridization [23].

References