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t(5;14)(q35;q32.2) BCL11B::TLX3 and NKX2-5

Written2008-05Stefan Nagel, Roderick AF MacLeod
DSMZ - German Collection of Microorganisms, Cell Cultures, Dept of Human & Animal Cell Cultures, Inhoffenstr. 7b, 38124, Braunschweig, Germany

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ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
Atlas_Id 1386

Clinics and Pathology

Disease T cell acute lymphoblastic leukemia (T-ALL)
Phenotype / cell stem origin Cortical T cell leukemia (CD1a+,CD10+)
Epidemiology Restricted to T-ALL. Relatively frequent in pediatric T-ALL (approximatively 20%); less frequent in adult T-ALL.
Cytology FAB nomenclature: L1 or L2 ALL
Prognosis TLX3 expression - presumably due to t(5;14)(q35.1;q32) or its congeners - has been reported to confer poor prognosis.


Cytogenetics Morphological t(5;14), like other cryptic chromosomal aberrations, was discovered relatively recently and most subsequent studies have focused on molecular and clinical aspects of this entity to the exclusion of cytogenetics. This gap is aggravated by the uniquely large breakpoint cluster region (bcr) of the 14q32 partner gene, BCL11B (alias CTIP2, RIT1). Hence, detailed documentation of this interesting rearrangement is largely based on data obtained using t(5;14) T-ALL cell lines which hitherto all carry submicroscopic insertions, both ins(5;14) and ins(14;5), instead of conventional reciprocal translocations. If verified in patient material, detailed analysis of such configurations may reveal neighboring genes or regulators inimical to the oncogenic activity of t(5;14), and therefore excluded by the more selective insertional rearrangements.
  G-banding of t(5;14)(q35;q32.2) in a pediatric T-ALL leukemia cell line (CCRF-CEM) illustrating the cryptic nature of this rearrangement. Hence normal and rearranged homologs are indistinguishable by G-banding, as are standard and rare variant t(5;14) subtypes. In chromosome painting images only a minority of cells in even superior preparations show the t(5;14).
Cytogenetics Molecular The proximities of the 14q32.2, and of both standard and variant 5q35 breakpoints to their respective telomeres, impairs FISH detection using chromosome painting probes except in optimal preparations. The tendency of t(5;14) to involve microinsertions (in both directions), together with the sheer magnitude of the BCL11B bcr, impedes detection by specific BAC/PAC combinations.
  Upper image depicts results of chromosome painting in an above average T-ALL cell (CCRF-CEM) with t(5;14) and concurrent ins(14;5). Note absence of visible signs betraying reciprocal exchange. Chromosome painting was performed using Cambio probes (Cambridge, UK) for chromosomes 5 (TexasRed), and 14 (Cy3). Middle image depicts standard t(5;14)(q35.1;q32.2) as represented by ins(5;14)(q35.1;q32.2q32.2) in cell line DND-41 which activates TLX3 transcription by juxtaposition with part of the noncoding region of BCL11B (clones shown below). Insert shows fiber-FISH confirming the regions juxtaposed. Lower image summarizes breakpoint data for t(5;14)(q35;q32) in T-ALL at three loci: TLX3 (standard translocation), NKX2-5 (variant translocation), and BCL11B (both translocations). Patient and cell line breakpoints are shown red and blue, respectively, together with insertion data from cell line DND-41. The NKX2-5 patient breakpoint included for comparison is from a t(5;14)(q35.2;q11.2) patient where TRAD is the activating partner. Coordinates are given in Mbp. Note the circa 1 Mbp 14q32.2 bcr which effectively covers the 3'-BCL11B regulatory region, while TLX3 breakpoints cover a "modest" 90 Kbp. NKX2-5 cases are too rare to allow bcr delineation.
Variants A microscopically synonymous variant, t(5;14)(q35.2;q32.2), whereby the closely related and neighboring NKX2-5 is juxtaposed to BCL11B, has proved frustratingly difficult to identify clinically despite occurring in two widely used T-ALL cell lines, CCRF-CEM and PEER. NKX2-5 is ectopically activated in t(5;14)(q35.2;q11.2) where it is juxtaposed with TRAD. The diagnostic caveats for the standard translocation also apply: detection of variant t(5;14) by RT-PCR is likely to pose fewer technical difficulties than cytogenetic detection by FISH.

Genes involved and Proteins

Note The breakpoints at 14q32.2 are located in the downstream region of BCL11B and are widely distributed along an almost unprecedentedly long stretch of about 1 Mbp in extent. So far there is no hint of deregulation of BCL11B by t(5;14)(q35;32). The t(5;14) aberration results in the juxtaposition of either TLX3 or NKX2-5 homeobox genes with enhancer elements located downstream of BCL11B inside a "genomic desert" region. TLX3 and NKX2-5 are located at 5q35.1 and 5q35.2, respectively, about 2 Mbp apart.
The centromeric neighbour of TLX3, RANBP17, may undergo truncation by the translocation, although this may not be significant as RANBP17 is not expressed in T-cells. While both, TLX3 and NKX2-5 have been described to be activated by translocations involving the T-cell receptor genes, aberrations targeting NKX2-5 seem to be very rare in T-ALL. Together with TLX1/HOX11 both homeobox genes, TLX3 and NKX2-5, are members of the NK-like family of homeobox genes, implicating similar activities in T-cell leukemogenesis. However, differences in the prognostic outcome may indicate functional differences between TLX1 and TLX3. A couple of dysregulated targets of these NK-like homeobox genes have been described, including PP2A for TLX1 and MEF2C for NKX2-5. Physiologically, TLX3 and NKX2-5 are involved in organogenesis of the spleen. Additionally, TLX3 is expressed in neuronal cells of the periphery and NKX2-5 in the heart. Therefore, their expression in T-cells is ectopic and serves as a solid diagnostic marker detectable by (quantitiative) RT-PCR. However, no standard assay for TLX3, as described for other mutated genes in leukemia/lymphoma by BIOMED, has been published so far.
Gene NameTLX3 (T-cell leukemia, homeobox protein 3)
Location 5q35.1
Note Alias: HOX11L2
Protein Homeodomain; member of the NK-like family of homeobox genes.
Gene NameNKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).
Location 5q35.1
Note Alias: CSX
Protein Homeodomain; member of the NK-like family of homeobox genes.

Result of the chromosomal anomaly

Hybrid gene
  Figure 1 shows RT-PCR analysis of genes involved in t(5;14)(q35;q32) in T-ALL cell lines PEER and CCRF-CEM, both expressing NKX2-5 instead of TLX3.
Figure 2 shows expression array data converted into a heat-map and demonstrate gene activities in five T-ALL cell lines: ALL-SIL (TRAD/TLX1), CCRF-CEM (NKX2-5/BCL11B), HPB-ALL (TLX3/BCL11B), PEER (NKX2-5/BCL11B), JURKAT (negative control). Red indicates high, green low, and black medium expression level. Note expression of homeobox genes is restricted to presence of corresponding translocation.
Fusion Protein
Description No fusion protein, but ectopic expression of either TLX3 or NKX2-5.
Oncogenesis Due to the chromosomal translocation, transcription factor binding sites for PU.1 and HMGA1, located near 5'-TLX3/NKX2-5 (5q35) and 3'-BCL11B (14q32.2), respectively, are juxtaposed. PU.1 and HMGA1 proteins are thus able to interact across the boundaries of the juxtaposed regions and form enhanceosomal complexes mediating transcriptional activity. Furthermore, BCL11B enhancer regions at 14q32 aggregate with acetylated histones recruited to open chromatin at DNaseI hypersensitive sites and contact the nuclear matrix - a region favorable to transcription. Altogether, these data indicate the existence of potent enhancer regions at 14q32 downstream of BCL11B responsible for homeobox gene activation in partipicipant translocations. The precise physiological mechanism(s) underlying the normal activity of presumptive BCL11B enhancers awaits clarification: although these enhancers may be involved in the developmental control of BCL11B activity - a gene demanding exquisite regulation in T-cells - little supporting data are as yet available.

To be noted

Additional cases are needed to delineate the epidemiology of this rare entity:
you are welcome to submit a paper to our new Case Report section.


A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia.
Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffe M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, Penard-Lacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R.
Leukemia. 2001 Oct;15(10):1495-504.
PMID 11587205
Clinical significance of HOX11L2 expression linked to t(5;14)(q35;q32), of HOX11 expression, and of SIL-TAL fusion in childhood T-cell malignancies: results of EORTC studies 58881 and 58951.
Cave H, Suciu S, Preudhomme C, Poppe B, Robert A, Uyttebroeck A, Malet M, Boutard P, Benoit Y, Mauvieux L, Lutz P, Méchinaud F, Grardel N, Mazingue F, Dupont M, Margueritte G, Pages MP, Bertrand Y, Plouvier E, Brunie G, Bastard C, Plantaz D, Vande Velde I, Hagemeijer A, Speleman F, Lessard M, Otten J, Vilmer E, Dastugue N; EORTC-CLG.
Blood. 2004 Jan 15;103(2):442-50. Epub 2003 Sep 22.
PMID 14504110
Significance of HOX11L2/TLX3 expression in children with T-cell acute lymphoblastic leukemia treated on Children's Cancer Group protocols.
Gottardo NG, Jacoby PA, Sather HN, Reaman GH, Baker DL, Kees UR.
Leukemia. 2005 Sep;19(9):1705-8.
PMID 15990867
BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia.
MacLeod RA, Nagel S, Drexler HG.
Cancer Genet Cytogenet. 2004 Aug;153(1):88-9.
PMID 15325104
Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2).
MacLeod RAF, Nagel S, Kaufmann M, Janssen JW, Drexler HG.
Genes Chromosomes Cancer. 2003 May;37(1):84-91.
PMID 12661009
The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2).
Nagel S, Kaufmann M, Drexler HG, MacLeod RA.
Cancer Res. 2003 Sep 1;63(17):5329-34.
PMID 14500364
MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines.
Nagel S, Meyer C, Quentmeier H, Kaufmann M, Drexler HG, MacLeod RA.
Leukemia. 2008 Mar;22(3):600-7. Epub 2007 Dec 13.
PMID 18079734
Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3'-BCL11B enhancers and coregulation by PU.1 and HMGA1.
Nagel S, Scherr M, Kel A, Hornischer K, Crawford GE, Kaufmann M, Meyer C, Drexler HG, MacLeod RA.
Cancer Res. 2007 Feb 15;67(4):1461-71.
PMID 17308084
The BCL11 gene family: involvement of BCL11A in lymphoid malignancies.
Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ.
Blood. 2001 Dec 1;98(12):3413-20.
PMID 11719382
Transforming potential of the T-cell acute lymphoblastic leukemia-associated homeobox genes HOXA13, TLX1, and TLX3.
Su X, Drabkin H, Clappier E, Morgado E, Busson M, Romana S, Soulier J, Berger R, Bernard OA, Lavau C.
Genes Chromosomes Cancer. 2006 Sep;45(9):846-55.
PMID 16804919
Various types of rearrangements target TLX3 locus in T-cell acute lymphoblastic leukemia.
Su XY, Busson M, Della Valle V, Ballerini P, Dastugue N, Talmant P, Ferrando AA, Baudry-Bluteau D, Romana S, Berger R, Bernard OA.
Genes Chromosomes Cancer. 2004 Nov;41(3):243-9.
PMID 15334547
HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32).
Su XY, Della-Valle V, Andre-Schmutz I, Lemercier C, Radford-Weiss I, Ballerini P, Lessard M, Lafage-Pochitaloff M, Mugneret F, Berger R, Romana SP, Bernard OA, Penard-Lacronique V.
Blood. 2006 Dec 15;108(13):4198-201. Epub 2006 Aug 22.
PMID 16926283
Cooperative genetic defects in TLX3 rearranged pediatric T-ALL.
Van Vlierberghe P, Homminga I, Zuurbier L, Gladdines-Buijs J, van Wering ER, Horstmann M, Beverloo HB, Pieters R, Meijerink JP.
Leukemia. 2008 Apr;22(4):762-70. Epub 2008 Jan 10.
PMID 18185524
Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences.
van Grotel M, Meijerink JP, van Wering ER, Langerak AW, Beverloo HB, Buijs-Gladdines JG, Burger NB, Passier M, van Lieshout EM, Kamps WA, Veerman AJ, van Noesel MM, Pieters R.
Leukemia. 2008 Jan;22(1):124-31. Epub 2007 Oct 11.
PMID 17928886


This paper should be referenced as such :
Nagel, S ; MacLeod, RAF
Atlas Genet Cytogenet Oncol Haematol. 2009;13(5):383-387.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 2 ]

Genes NKX2-5 VRK1

Translocations implicated (Data extracted from papers in the Atlas)

 t(5;14)(q35;q32.2) BCL11B/TLX3 and NKX2-5

External links

Mitelman databaset(5;14)(q35;q32.2)
arrayMap (UZH-SIB Zurich)Topo ( C42) Morph ( 9837/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
REVIEW articlesautomatic search in PubMed
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