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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). Roderick AF MacLeod, Stefan Nagel DSMZ - Deutsche Sammlung von Mikroorganismen und Zellkulturen, Mascheroder Weg 1b 38124, Braunschweig, Germany (RAFM, SN) Published in Atlas Database: March 2005 Online updated version: http://AtlasGeneticsOncology.org/Genes/NKX25ID42958ch5q35.html DOI: 10.4267/2042/38185 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2005 Atlas of Genetics and Cytogenetics in Oncology and Haematology Pseudogene Identity Not known. Other names: CSX; CSX1; NKX2E; Hs.54473; NM_004387; cardiac-specific homeobox HGNC (Hugo): NKX2-5 Location: 5q35.2 Local order: cen--- BNIP1---NKX2-5--- STC2---tel. Protein Description 324 amino acids; 35-38 kDa, depending on phosphorylation status; contains one TN domain (residues 10-21), one homeodomain (residues 138197), and one NK2 domain (residues 212-234). DNA/RNA Description Expression The gene has two exons and one intron. Expression is mainly restricted to the heart. But during embryogenesis NKX2-5 expression has also been detected in spleen-precursor cells. Transcription Transcription takes place in a telomere --> centromere orientation. The length of the processed mRNA is about 1500 bp. Localisation Cytoplasmatic and nuclear, probably depending on phosphorylation status. The gene for NKX2-5 comprizes two exons of 510 and 1075 bp, respectively. The length of the intron is 1540 bp. Positions of start and stop codons are indicated. These data refer to ENSEMBL transcript. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) 139 NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). MacLeod RAF, Nagel S Figure shows mutations causing various cardiac anomalies. NKX2-5 contains two exons encoding a 324-amino acid protein including a tinman domain (TN), homeodomain (black) and an NK2 domain. Truncation mutations are shown above, missense mutations below. ∆ indicates deletion of the intron 1 splice donor site. Note clustering of mutations within the homeobox itself. Function Prognosis Unknown. Cytogenetics The t(5;14) rearrangements respectively targeting NKX2-5 and TLX3 which lies about 2Mbp centromeric are cytogenetically indistinguishable in both conventionally banded and chromosome painting preparations. In addition, both sets of rearrangements are cryptic as equal and similarly banded material from chromosomes 5 and 14 are exchanged. Thus, analysis using sets of BAC clones covering both TLX3 and NKX2-5 loci is necessary to distinguish these rearrangements. Hybrid/Mutated gene No. Involved in differentiation processes in heart development and in homeostasis and survival of cardiac myocytes. Homology Homeodomain protein with membership of the NK2 / NKX family. Mutations Note Among vertebrates, NKX2-5 is the most highly conserved of the Drosophila tinman homologs and subject to transcriptional control via complex series of cis-regulatory elements both proximal and distal of the transcription unit. Germinal Haploinsufficiency due to loss-of-function mutations is associated with atrioventricular conduction defects and tetralogy of Fallot. Somatic Recently identified in cardiac disease. Implicated in t(5;14)(q35;q32) in acute lymphoblastic leukaemia (ALL) and t(5;14)(q35;q11) in chronic lymphocytic leukaemia Note NKX2-5 lies circa 2 Mbp telomeric of TLX3 which is recurrently targeted for juxtaposition with BCL11B by t(5;14)(q35;q32) in a subset of patients (both pediatric and adult) in T-cell ALL. Studies performed on pediatric T-ALL cell lines have shown that visually identical t(5;14) rearrangements may target NKX2-5 or TLX3 . Initial data suggest that the t(5;14) variant targeting NKX2-5 is clinically rare. The clinical involvement t(5;14)/NKX2-5 has only been recently identified but has yet to be published. In addition to TALL, NKX2-5 rearrangement has been reported in a case of chronic lymphocytic leukaemia (CLL) with t(5;14)(q35;q11) where the activating partner at 14q11 is TCRA/TCRD. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) Figure shows FISH analysis of t(5;14) in the pediatric T-ALL cell line PEER using three RP11 library clones located immediately centromeric (779o18, labelled red), spanning (466h21, green) and telomeric (45g21, yellow) of NKX2-5. (See below for map.) The rearrangement may be a simple insertion or, a double translocation whereby chromosome 14 material is first translocated onto the der(5) and then returned by a nonreciprocal copying process to the der(14) accompanied by genomic material surrounding NKX2-5. 140 NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). MacLeod RAF, Nagel S regulatory region of BCL11B which plays a central role in thymic maturation. It is believed that both TLX3 and NKX2-5 are reactivated by similar mechanisms involving juxtaposition with T-cell specific regulatory regions. Structural similarities shared by NKX2-5, TLX1 and TLX3 add weight to this hypothesis. Abnormal protein No Oncogenesis NKX2-5 is developmentally silenced in thymocytes. Formation of t(5;14) juxtaposes NKX2-5 with enhancer elements probably cognate with T-cell specific DNaseI hypersensitive sites present in the downstream Breakpoints Figure shows breakpoints described in ALL cell lines with t(5;14)(q35.2;q32) which juxtaposes NKX2-5 with the downstream region of BCL11B - outer breakpoints; and in a case of CLL with t(5;14)(q35.2;q11) where the activating locus was TRD - middle breakpoint. Completion of sequencing data at the NKX2-5 locus has repositioned some of the BAC clones, allowing further refinement of the breakpoint assignments. It is now clear that known breakpoints tightly flank NKX2-5 without disrupting the transcription unit itself. Thus, NKX2-5 translocations may also involve disruption of cis-regulatory elements as has been shown for TLX1(HOX11) in t(10;14)(q24;q11) in T-ALL. References Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development. 1993 Oct;119(2):419-31 Bernard OA, Busson-LeConiat M, Ballerini P, Mauchauffé M, Della Valle V, Monni R, Nguyen Khac F, Mercher T, PenardLacronique V, Pasturaud P, Gressin L, Heilig R, Daniel MT, Lessard M, Berger R. 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. Leukemia. 2001 Oct;15(10):1495-504 Harvey RP. NK-2 homeobox genes and heart development. Dev Biol. 1996 Sep 15;178(2):203-16 Tanaka M, Kasahara H, Bartunkova S, Schinke M, Komuro I, Inagaki H, Lee Y, Lyons GE, Izumo S. Vertebrate homologs of tinman and bagpipe: roles of the homeobox genes in cardiovascular development. Dev Genet. 1998;22(3):239-49 Berger R, Dastugue N, Busson M, Van Den Akker J, Pérot C, Ballerini P, Hagemeijer A, Michaux L, Charrin C, Pages MP, Mugneret F, Andrieux J, Talmant P, Hélias C, Mauvieux L, Lafage-Pochitaloff M, Mozziconacci MJ, Cornillet-Lefebvre P, Radford I, Asnafi V, Bilhou-Nabera C, Nguyen Khac F, Léonard C, Speleman F, Poppe B, Bastard C, Taviaux S, Quilichini B, Herens C, Grégoire MJ, Cavé H, Bernard OA. t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Français de Cytogénétique Hématologique (GFCH). Leukemia. 2003 Sep;17(9):1851-7 Kasahara H, Izumo S. Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5. Mol Cell Biol. 1999 Jan;19(1):526-36 Schwartz RJ, Olson EN. Building the heart piece by piece: modularity of cis-elements regulating Nkx2-5 transcription. Development. 1999 Oct;126(19):4187-92 Hatcher CJ, Kim MS, Basson CT. Atrial form and function: lessons from human molecular genetics. Trends Cardiovasc Med. 2000 Apr;10(3):93-101 MacLeod RA, Nagel S, Kaufmann M, Janssen JW, Drexler HG. Activation of HOX11L2 by juxtaposition with 3'-BCL11B in an acute lymphoblastic leukemia cell line (HPB-ALL) with t(5;14)(q35;q32.2). Genes Chromosomes Cancer. 2003 May;37(1):84-91 Patterson KD, Drysdale TA, Krieg PA. Embryonic origins of spleen asymmetry. Development. 2000 Jan;127(1):167-75 Nagel S, Kaufmann M, Drexler HG, MacLeod RA. The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) 141 NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila). MacLeod RAF, Nagel S BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res. 2003 Sep 1;63(17):5329-34 MacLeod RA, Nagel S, Drexler HG. BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia. Cancer Genet Cytogenet. 2004 Aug;153(1):88-9 Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y, Hitomi J, Yamamoto T, Utsuyama M, Niwa O, Aizawa S, Kominami R. Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Nat Immunol. 2003 Jun;4(6):533-9 Reamon-Buettner SM, Hecker H, Spanel-Borowski K, Craatz S, Kuenzel E, Borlak J. Novel NKX2-5 mutations in diseased heart tissues of patients with cardiac malformations. Am J Pathol. 2004 Jun;164(6):2117-25 Brake RL, Chatterjee PK, Kees UR, Watt PM. The functional mapping of long-range transcription control elements of the HOX11 proto-oncogene. Biochem Biophys Res Commun. 2004 Jan 9;313(2):327-35 Su X, Busson M, Delabessee E, Azgui Z, Berger R, Beral HM, Bernard OA. Transcriptional activation of the cardiac homeobox gene CSX1/NKX2-5. Blood. 2004;104:p152. van Zutven LJ, Velthuizen SC, Wolvers-Tettero IL, van Dongen JJ, Poulsen TS, MacLeod RA, Beverloo HB, Langerak AW. Two dual-color split signal fluorescence in situ hybridization assays to detect t(5;14) involving HOX11L2 or CSX in T-cell acute lymphoblastic leukemia. Haematologica. 2004 Jun;89(6):671-8 Crawford GE, Holt IE, Mullikin JC, Tai D, Blakesley R, Bouffard G, Young A, Masiello C, Green ED, Wolfsberg TG, Collins FS. Identifying gene regulatory elements by genome-wide recovery of DNase hypersensitive sites. Proc Natl Acad Sci U S A. 2004 Jan 27;101(4):992-7 Jay PY, Harris BS, Buerger A, Rozhitskaya O, Maguire CT, Barbosky LA, McCusty E, Berul CI, O'brien TX, Gourdie RG, Izumo S. Function follows form: cardiac conduction system defects in Nkx2-5 mutation. Anat Rec A Discov Mol Cell Evol Biol. 2004 Oct;280(2):966-72 Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2) This article should be referenced as such: MacLeod RAF, Nagel S. NKX2-5 (NK2 transcription factor related, locus 5 (Drosophila).. Atlas Genet Cytogenet Oncol Haematol. 2005; 9(2):139-142. 142