Disease relevance of TLX3

• A cryptic chromosome rearrangement, t(5;14)(q35.1;q32.2), recently identified in pediatric acute lymphoblastic leukemia (ALL), targets activation of TLX3 at 5q35.1 by juxtaposition with a region downstream of BCL11B at 14q32 [1].
• This study further underscores that TLX3 expression in T-ALL is strongly associated with the presence of genomic rearrangements [2].
• Finally, our data show that HOX11L2 expression was a suitable marker for minimal residual disease follow-up and was significantly associated with relapse (P =.02) [3].
• Mutational analysis of the RNX gene in congenital central hypoventilation syndrome [4].
• Based on this observation, we have carried out mutation screening of the RNX gene in a set of 13 patients affected with CCHS, 2 of whom showing association with Hirschsprung disease [4].

High impact information on TLX3

• Our data indicate that the basis of the specific association between t(5;14) and T-ALL lies on the juxtaposition of TLX3 to long-range cis-activating regions active during T-cell differentiation [5].
• By transient transfection experiments, 2 of the 6 regions demonstrated cis-activation properties in T cells and were also effective on the TLX3 promoter [5].
• HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32) [5].
• 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 [6].
• Once CR was obtained, cumulative relapse rates were similar for IM, pre-alphabeta, and TCR+ T-ALL patients (P = .51), but were higher in HOX11L2 (83%) and SIL-TAL1 (82%) T-ALL patients compared with other genetic subgroups (48%; P = .05) [7].

Biological context of TLX3

• To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients [8].
• Single-strand conformational polymorphism analysis and direct sequencing of the whole coding portion of the RNX gene and of 1,311 bp of 5' flanking region were performed [4].
• Assignment of the HOX11L2 gene to human chromosome band 5q35.1 and of its murine homolog to mouse chromosome bands 11A4-A5 by in situ hybridization [9].
• INTERPRETATION AND CONCLUSIONS: Using the newly developed and validated FISH probe sets, we identified 5 new cases of t(5;14) involving HOX11L2 both on metaphases and interphases [10].
• 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 [11].

Anatomical context of TLX3

• Various types of rearrangements target TLX3 locus in T-cell acute lymphoblastic leukemia [2].
• Based on a knocked-out mouse model and a few expression studies, TLX3 is regarded as a homeobox gene crucial for the development of the autonomic nervous system [12].
• Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2) [13].

Associations of TLX3 with chemical compounds

• Nuclear Factor Y Drives Basal Transcription of the Human TLX3, a Gene Overexpressed in T-Cell Acute Lymphocytic Leukemia [12].

Regulatory relationships of TLX3

• In this t(5;14) variant, NKX2-5 is expressed instead of TLX3 at both RNA and protein levels [1].

Other interactions of TLX3

• However, in a myeloid clonogenic assay HOXA13 and TLX3 extended the proliferation of progenitors similarly to what was observed for TLX1 [14].
• Cotransduction of the HOX cofactor MEIS1 with TLX3 or HOXA13 did not alter this outcome [14].
• The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11 [15].
• Involvement of the RANBP17/HOX11L2 locus was ascertained by fluorescence in situ hybridization in six variant or alternative (three-way translocation or cytogenetic partner other than 14q32) translocations out of the 223 patients [8].
• Here we describe the development and application of split signal fluorescence in situ hybridization (FISH) assays for both HOX11L2 and CSX, for detection of t(5;14) possibly present in T-ALL patients [10].

Analytical, diagnostic and therapeutic context of TLX3

• The 3-year event-free survival (EFS) rate (+/- SE percentage) for patients positive and negative for HOX11L2/t(5;14) was 75.5% (+/- 8.1%) and 68.3% (+/- 5.0%), respectively; the hazard ratio was 0.84 (95% confidence interval, 0.40-1.80) [16].
• Assignment of the human homeobox 11-like 2 gene (HOX11L2) to chromosome 5q34-->q35 by radiation hybrid mapping [17].
• Homeobox (HOX) 11 and HOX11L2 expression was determined by real-time PCR [18].

References