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t(1;9)(p13;p12) PAX5/HIPK1

Written2014-02Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1557

Clinics and Pathology

Disease B-cell acute lymphoblastic leukemia (B-ALL)
Epidemiology Only one case to date, a 3-year old boy with a CD10+ ALL (Nebral et al., 2009).
Prognosis The patient was noted at an intermediate risk, and was in complete remission 6 months after diagnosis.

Genes involved and Proteins

Gene NameHIPK1 (homeodomain interacting protein kinase 1)
Location 1p13.2
Protein 1210 amino acids (aa). From N-term to C-term, contains a protein kinase domain (aa 190-518), a nucleotide binding motif (aa 196-204), a domain interacting with DAB2IP (AIP1, or AF9q34, 9q33.2) (aa 518-889), a nuclear localization signal (aa 844-847), a region interacting with TP53 (aa 885-1093), a nuclear speckle retention signal (aa 887-992), (corresponding to aa 860-967 in HIPK2), a PEST domain (enriched in proline (P), glutamate (E), serine (S), and threonine (T), expedite the degradation of proteins) (aa 892-972), SUMO interaction motifs, required for nuclear localization and kinase activity (aa 902-926), a domain interacting with DAB2IP/MAP3K5 (aa 973-1209), a histidine-rich region (aa 1086-1154), and a tyrosine-rich region (aa 1175-1209) (YH region). The lysine residues at the sumoylation motifs are the following: K25, K317, K440, K556, and K1202 (Kim et al., 1998; Li et al., 2005; Swiss-Prot).
First identified as a nuclear serine/threonine kinase. Homeodomain-interacting protein kinase. HIPK1 positively or negatively modulate signaling pathways controlling cell proliferation and/or apoptosis (review in Rinaldo et al., 2008). HIPK1 and HIPK2 act cooperatively as corepressors in the transcriptional activation of angiogenic genes, including MMP10 (11q22.2) and VEGFA (6p21.1), that are critical for the early stage of vascular development (Shang et al., 2013). HIPK1 regulates the p53 signaling pathway. PARK7 (also called DJ-1, 1p36.23), a protein also linked to the p53 signaling pathway, is able to induce HIPK1 degradation. HIPK1 directly phophorylates TP53 on its serine-15. Serine 15 phosphorylation induces a rise in CDKN1A (p21, 6p21.2) expression and cell cycle arrest (Rey et al., 2013). HIPK1 phosphorylates DAXX (6p21.32), a protein which interacts with PML (15q24.1), the organizer of nuclear bodies (Ecsedy et al., 2003), and which relocalizes from the nucleus to the cytoplasm in response to stress. During glucose deprivation, a pathway involving MAP3K5 (also called ASK1, 6q23.3), -> MAP2K4 (SEK1, 17p12) -> MAPK8 (JNK1, 10q11.22) -> HIPK1 is activated, and DAXX is relocated in the cytoplasm (Song and Lee, 2003). TNF (TNF-alpha, 6p21.33) induces desumoylation and cytoplasm translocation of HIPK1 leading to apoptosis (Li et al., 2005). HIPK1 and HIPK2 bind HOX genes homeodomains and regulate their expression, as well as PAX1 (20p11.22) and PAX3 (2q36.1) transcription (Isono et al., 2006). HIPK1 and HIPK2 phosphorylates EP300 (22q13.2) and RUNX1 (21q22.12) during embryonic development, and Hipk1/Hipk2-deficient mice show defective definitive hematopoiesis (Aikawa et al., 2006). HIPK1 phosphorylates MYB (6q23.3), a transcriptional activator essential for the establishment of haemopoiesis, and causes repression of MYB activation (Matre et al., 2009). HIPK1 interacts with DVL1 (1p36.33) and TCF3 (E2A, 19p13.3) and regulates Wnt/b-catenin target genes during early embryonic development (Louie et al., 2009). HIPK1 is highly overexpressed in colorectal carcinomas compared with healthy mucosa. The highest peak of HIPK1 expression occurred at early stages and decreased in latter stages. HIPK1 appeared to be induced as a defense mechanism to fight against intern deregulations and stressful conditions, rather than produced by the cancer cells as an indispensable factor for tumor evolution (Rey et al., 2013). HIPK1 is expressed only in invasive breast cancer cells with three different subcellular localization, associated with different tumor histopathologic characteristics (Park et al., 2012).
Gene NamePAX5 (paired box gene 5)
Location 9p13.2
Protein 391 amino acids; from N-term to C-term, PAX5 contains: a paired domain (aa: 16-142); an octapeptide (aa: 179-186); a partial homeodomain (aa: 228-254); a transactivation domain (aa: 304-359); and an inhibitory domain (aa: 359-391). Lineage-specific transcription factor; recognizes the concensus recognition sequence GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of common lymphoid progenitors into the B cell lineage depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other lineage commitments. Activates the surface cell receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007; Medvedovic et al., 2011).

Result of the chromosomal anomaly

Hybrid gene
Description Fusion of PAX5 exon 5 to HIPK1 exon 9.
  
Fusion Protein
 
  t(1;9)(p13;p13) PAX5/HIPK1 fusion protein.
Description 751 amino acids. The predicted fusion protein contains the DNA binding paired domain of PAX5 and the nuclear localization signal, the region interacting with TP53, the nuclear speckle retention signal, the PEST domain, the SUMO interaction motifs, the domain interacting with DAB2IP/MAP3K5, and theYH region from HIPK1.
  

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

Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation.
Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y, Schmitz ML, Koseki H, Kitabayashi I.
EMBO J. 2006 Sep 6;25(17):3955-65. Epub 2006 Aug 17.
PMID 16917507
 
Pax5: the guardian of B cell identity and function.
Cobaleda C, Schebesta A, Delogu A, Busslinger M.
Nat Immunol. 2007 May;8(5):463-70. (REVIEW)
PMID 17440452
 
Homeodomain-interacting protein kinase 1 modulates Daxx localization, phosphorylation, and transcriptional activity.
Ecsedy JA, Michaelson JS, Leder P.
Mol Cell Biol. 2003 Feb;23(3):950-60.
PMID 12529400
 
Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene.
Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M.
Genes Dev. 2004 Feb 15;18(4):411-22.
PMID 15004008
 
Overlapping roles for homeodomain-interacting protein kinases hipk1 and hipk2 in the mediation of cell growth in response to morphogenetic and genotoxic signals.
Isono K, Nemoto K, Li Y, Takada Y, Suzuki R, Katsuki M, Nakagawara A, Koseki H.
Mol Cell Biol. 2006 Apr;26(7):2758-71.
PMID 16537918
 
B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5.
Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Thomas-Tikhonenko A, Schatz DG, Calame K.
Nat Immunol. 2004 Aug;5(8):853-61. Epub 2004 Jul 18.
PMID 15258579
 
Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors.
Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y.
J Biol Chem. 1998 Oct 2;273(40):25875-9.
PMID 9748262
 
Tumor necrosis factor alpha-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation.
Li X, Zhang R, Luo D, Park SJ, Wang Q, Kim Y, Min W.
J Biol Chem. 2005 Apr 15;280(15):15061-70. Epub 2005 Feb 8.
PMID 15701637
 
Modulation of the beta-catenin signaling pathway by the dishevelled-associated protein Hipk1.
Louie SH, Yang XY, Conrad WH, Muster J, Angers S, Moon RT, Cheyette BN.
PLoS One. 2009;4(2):e4310. doi: 10.1371/journal.pone.0004310. Epub 2009 Feb 2.
PMID 19183803
 
HIPK1 interacts with c-Myb and modulates its activity through phosphorylation.
Matre V, Nordgard O, Alm-Kristiansen AH, Ledsaak M, Gabrielsen OS.
Biochem Biophys Res Commun. 2009 Oct 9;388(1):150-4. doi: 10.1016/j.bbrc.2009.07.139. Epub 2009 Jul 30.
PMID 19646965
 
Pax5: a master regulator of B cell development and leukemogenesis.
Medvedovic J, Ebert A, Tagoh H, Busslinger M.
Adv Immunol. 2011;111:179-206. doi: 10.1016/B978-0-12-385991-4.00005-2. (REVIEW)
PMID 21970955
 
Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia.
Nebral K, Denk D, Attarbaschi A, Konig M, Mann G, Haas OA, Strehl S.
Leukemia. 2009 Jan;23(1):134-43. doi: 10.1038/leu.2008.306. Epub 2008 Nov 20.
PMID 19020546
 
Homeodomain-interacting protein kinase 1 (HIPK1) expression in breast cancer tissues.
Park BW, Park S, Koo JS, Kim SI, Park JM, Cho JH, Park HS.
Jpn J Clin Oncol. 2012 Dec;42(12):1138-45. doi: 10.1093/jjco/hys163. Epub 2012 Oct 15.
PMID 23071292
 
HIPK1 drives p53 activation to limit colorectal cancer cell growth.
Rey C, Soubeyran I, Mahouche I, Pedeboscq S, Bessede A, Ichas F, De Giorgi F, Lartigue L.
Cell Cycle. 2013 Jun 15;12(12):1879-91. doi: 10.4161/cc.24927. Epub 2013 May 15.
PMID 23676219
 
HIPKs: Jack of all trades in basic nuclear activities.
Rinaldo C, Siepi F, Prodosmo A, Soddu S.
Biochim Biophys Acta. 2008 Nov;1783(11):2124-9. doi: 10.1016/j.bbamcr.2008.06.006. Epub 2008 Jun 18. (REVIEW)
PMID 18606197
 
Transcriptional corepressors HIPK1 and HIPK2 control angiogenesis via TGF-b-TAK1-dependent mechanism.
Shang Y, Doan CN, Arnold TD, Lee S, Tang AA, Reichardt LF, Huang EJ.
PLoS Biol. 2013;11(4):e1001527. doi: 10.1371/journal.pbio.1001527. Epub 2013 Apr 2.
PMID 23565059
 
Role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx trafficking and ASK1 oligomerization.
Song JJ, Lee YJ.
J Biol Chem. 2003 Nov 21;278(47):47245-52. Epub 2003 Sep 10.
PMID 12968034
 
Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes.
Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD.
Nat Immunol. 2006 Jun;7(6):616-24. Epub 2006 May 7.
PMID 16680144
 

Citation

This paper should be referenced as such :
JL Huret
t(1;9)(p13;p12) PAX5/HIPK1
Atlas Genet Cytogenet Oncol Haematol. 2014;18(9):685-687.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0109p13p12ID1557.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(1;9)(p13;p12) PAX5/HIPK1

External links

PAX5 (9p13.2) HIPK1 (1p13.2)

PAX5 (9p13.2) HIPK1 (1p13.2)

Mitelman databaset(1;9)(p13;p12) [Case List]    t(1;9)(p13;p12) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
Mitelman databasePAX5/HIPK1 [MCList]  PAX5 (9p13.2) HIPK1 (1p13.2)
TICdbPAX5/HIPK1  PAX5 (9p13.2) HIPK1 (1p13.2)
 
Disease databaset(1;9)(p13;p12) PAX5/HIPK1
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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indexed on : Tue Nov 21 15:08:58 CET 2017


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