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t(5;9)(q35;q34) SQSTM1/NUP214

Written2018-08Jean-Loup Huret
jean-loup.huret@atlasgeneticsoncology.org

Abstract Review on t(5;9)(q35;q34), with data on clinics, and the genes involved.

Keywords Chromosome 5; chromosome 9; SQSTM1; NUP214; T-cell acute lymphoblastic leukemia; acute myeloid leukemia.

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho 9861/3 AML with mutated NPM1; AML with mutated CEBPA; Acute myeloid leukaemia, NOS
Atlas_Id 1833

Clinics and Pathology

Disease T-cell acute lymphoblastic leukemia and acute myeloid leukemia.
Clinics The t(5;9)(q35;q34) SQSTM1/NUP214 was found in a 12-year old boy with early T-cell precursor acute lymphoblastic leukaemia (lack of expression of the T-lineage cell surface markers CD1a and CD8, weak or absent expression of CD5, aberrant expression of myeloid and haematopoietic stem cell markers). Outcome: the patient was alive at the time of the report (Zhang et al. 2012), in a 20-year old man, with a chemoresistant pre-T ALL (CD3+, CD7+, CD5+, CD34+, CD33+, cKit+) who died 16 months after diagnosis (Gorello et al., 2010), and in a pediatric acute myeloid leukemia not otherwise specified (AML-NOS) case; outcome was remission (Brown et al., 2017)

Cytogenetics

Cytogenetics Morphological Cryptic unbalanced translocation (Gorello et al., 2010).
Additional anomalies del(13q) and other abnormalities (complex karyotype) were found in the early T-cell precursor acute lymphoblastic leukemia case. del(6p) was found in the other T-cell case, and also CDKN2A - CDKN2B /9p21 and NF1/17q11 deletions.

Genes involved and Proteins

Gene NameSQSTM1 (sequestosome 1)
Location 5q35.3
Protein 440 amino acids (aa). SQSTM1 (sequestosome 1), also called p62, is a scaffolding protein with several interaction domains; it is composed of an OPR domain (octatricopeptide repeat (PB1 dimerization domain)), a Zn finger, a LIM protein-binding region, a TRAF6-binding motif, a PEST sequence (proline, glutamic acid, serine, and threonine rich), a LIR motif (LC3 interaction region, SGGDDDWTHLSS), a second PEST sequence, a KIR (keap1 interacting region), and an UBA (ubiquitin-associated) domain. Interacts with Caspase-8 and the apoptosis, machinery, MAPK kinases such as MAP2K5 (15q23), LCK (1p34), NBR1 (17q21), PRKCI (3q26), PAWR (12q21), RIPK1 (6p25), TRAF6 (11p12) and NTRK1 (1q23) and the NF-kappaB pathway, KEAP1 (19p13), GABARAPL1 (12p13), MAP1LC3A/LC3 (20q11), and ubiquitin. Mediates the interaction between TRAF6 and CYLD (16q12). Implicated in the activation of the transcription factor NF-kappaB. Involved in the autophagy-lysosome pathway. Plays a role in the formation of cytoplasmic proteinaceous inclusions in various pathologic situations where autophagy is inactivated (Geetha and Wooten, 2002; Lamark et al., 2009; Moscat and Diaz-Meco, 2009; Moscat et al., 2009; Ichimura and Komatsu, 2010; Komatsu and Ichimura, 2010; Moscat and Diaz-Meco, 2011).
Germinal mutations Mutated in Paget's disease of bone.
Gene NameNUP214 (nucleoporin 214kDa)
Location 9q34.13
Note The previous name of NUP214 was CAN.
Protein 2090 aa; contains dimerization domains (leucine zippers and FG repeats). The NUP214 N-terminal domain (NTD, aa 1-450) is composed of the seven-bladed β-propeller domain (aa 41-405), with, in particular, the 6D7A loop, an inter-blade connector loop that encompasses 20 residues (aa 342-361: LLEDSSRAELPVTDKSDDSL), followed by the 30-residue C-terminal extension (CTE aa 405-434) that binds to the bottom face of the β-propeller, followed by a flexible linker, the coiled-coil domain (aa 680-1209) with two leucine-zippers (aa 740-768 and 861-882), and the C-terminal region with numerous FG-repeats (phenylalanine-glycine repeat motifs, aa 1809-2090). The CTE contains several putative phosphorylation sites, including Ser-430 and Thr-437. Component of the nuclear pore complex involved in nucleo-cytoplasmic transport. NUP214 is localized in the nuclear membrane, on the cytoplasmic face of the nucleopore complex. NUP214, NUP88 and XPO1 form a subcomplex which anchors the cytoplasmic fibrils to the nuclear pore complex.
The N-terminal region of NUP214 is involved in mRNA export: it has been found to interact with the DEAD box helicase DDX19, and mutations in DDX19 that disrupt binding to NUP214 inhibit mRNA export The 6D7A loop of the NUP214 NTD is required for complex formation with DDX19. (Köser et al., 2005; Napetschnig et al., 2007; Napetschnig et al., 2009).

Result of the chromosomal anomaly

Hybrid gene
Description SQSTM1 nucleotide 849 (exon 5) is fused in-frame to NUP214 nucleotide 6014 (exon 33). Same breakpoints in Zhang et al. 2012 and in Gorello et al., 2010.
  
Fusion Protein
 
  NUP214, SQSTM1, and SQSTM1/NUP214 fusion protein.
Description SQSTM1/NUP214 fusion protein is composed of 374 aa with 251 N-term aa from SQSTM1 and 123 C-term aa de NUP214. Interaction domain with LCK; OPR; Zinc finger; LIM-binding; and TRAF6-binding domains from SQSTM1 are fused to (only) 14 of the 44 FG repeats of NUP214. SQSTM1/NUP214 had not maintained the entire XPO1 binding domain of NUP214, and other mechanisms might be implicated in the leukemogenic process (Gorello et al., 2010).
  

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.

Bibliography

Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia.
Brown FC, Cifani P, Drill E, He J, Still E, Zhong S, Balasubramanian S, Pavlick D, Yilmazel B, Knapp KM, Alonzo TA, Meshinchi S, Stone RM, Kornblau SM, Marcucci G, Gamis AS, Byrd JC, Gonen M, Levine RL, Kentsis A.
Br J Haematol. 2017 Jan;176(1):86-91. doi: 10.1111/bjh.14413. Epub 2016 Oct 21.
PMID 27766616
 
Structure and functional properties of the ubiquitin binding protein p62.
Geetha T, Wooten MW.
FEBS Lett. 2002 Feb 13;512(1-3):19-24.
PMID 11852044
 
SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia.
Gorello P, La Starza R, Di Giacomo D, Messina M, Puzzolo MC, Crescenzi B, Santoro A, Chiaretti S, Mecucci C.
Haematologica. 2010 Dec;95(12):2161-3. doi: 10.3324/haematol.2010.029769. Epub 2010 Sep 17. No abstract available.
PMID 20851865
 
Selective degradation of p62 by autophagy.
Ichimura Y, Komatsu M.
Semin Immunopathol. 2010 Dec;32(4):431-6. Epub 2010 Sep 3. (REVIEW)
PMID 20814791
 
Physiological significance of selective degradation of p62 by autophagy.
Komatsu M, Ichimura Y.
FEBS Lett. 2010 Apr 2;584(7):1374-8. Epub 2010 Feb 12. (REVIEW)
PMID 20153326
 
The nuclear pore complex becomes alive: new insights into its dynamics and involvement in different cellular processes.
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Lamark T, Kirkin V, Dikic I, Johansen T.
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PMID 19502794
 
Of the atypical PKCs, Par-4 and p62: recent understandings of the biology and pathology of a PB1-dominated complex.
Moscat J, Diaz-Meco MT, Wooten MW.
Cell Death Differ. 2009 Nov;16(11):1426-37. Epub 2009 Aug 28. (REVIEW)
PMID 19713972
 
Structural and functional analysis of the interaction between the nucleoporin Nup214 and the DEAD-box helicase Ddx19.
Napetschnig J, Kassube SA, Debler EW, Wong RW, Blobel G, Hoelz A.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3089-94. doi: 10.1073/pnas.0813267106. Epub 2009 Feb 10.
PMID 19208808
 
The genetic basis of early T-cell precursor acute lymphoblastic leukaemia.
Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, Lu C, Chen SC, Wei L, Collins-Underwood JR, Ma J, Roberts KG, Pounds SB, Ulyanov A, Becksfort J, Gupta P, Huether R, Kriwacki RW, Parker M, McGoldrick DJ, Zhao D, Alford D, Espy S, Bobba KC, Song G, Pei D, Cheng C, Roberts S, Barbato MI, Campana D, Coustan-Smith E, Shurtleff SA, Raimondi SC, Kleppe M, Cools J, Shimano KA, Hermiston ML, Doulatov S, Eppert K, Laurenti E, Notta F, Dick JE, Basso G, Hunger SP, Loh ML, Devidas M, Wood B, Winter S, Dunsmore KP, Fulton RS, Fulton LL, Hong X, Harris CC, Dooling DJ, Ochoa K, Johnson KJ, Obenauer JC, Evans WE, Pui CH, Naeve CW, Ley TJ, Mardis ER, Wilson RK, Downing JR, Mullighan CG.
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Citation

This paper should be referenced as such :
Huret JL
t(5;9)(q35;q34) SQSTM1/NUP214;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0509q35q34ID1833.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(5;9)(q35;q34) SQSTM1/NUP214

External links

Mitelman databaset(5;9)(q35;q34) [Case List]    t(5;9)(q35;q34) [Transloc-MCList] SQSTM1/NUP214 [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Morph ( 9837/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9861/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
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