dic(9;12)(p13;p13) PAX5/ETV6

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Written1997-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2003-06Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2004-01Sabine Strehl
CCRI, Children's Cancer Research Institute St. Anna Kinderkrebsforschung Kinderspitalgasse 6 A-1090, Vienna, Austria
Updated2017-01Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France; jean-loup.huret@chu-poitiers.fr

Abstract Review on dic(9;12)(p13;p13) PAX5/ETV6, with data on clinics and the genes involved.

Keywords Chromosome 9; chromosome 12; Acute lymphoblastic leukemia; PAX5; ETV6.

(Note : for Links provided by Atlas : click)

1. Identity

ICD-Topo C420,C421,C424
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
ICD-Morpho 9837/3 T lymphoblastic leukaemia/lymphoma
ICD-Morpho 9975/3 Chronic myelogenous leukaemia, BCR-ABL1 positive; Myeloproliferative neoplasm, unclassifiable; Myelodysplastic/myeloproliferative neoplasm, unclassifiable
ICD-Morpho 9823/3 Chronic lymphocytic leukaemia /small lymphocytic lymphoma
Atlas_Id 1065
Note The fusion of PAX5 and ETV6 in the dic(9;12)(p13;p13) was first described by Strehl et al., 2003. PAX5/ETV6 fusion was found in 18/19 (95%) dic(9;12) cases in a study by An et al., 2008, and one case was a dic(9;12)(p13;p12) with a PAX5/SLCO1B3 fusion.
  dic(9;12)(p13;p13) Top row: G- banding - Courtesy Jean-Luc Lai (left) and Diane H. Norback, Eric B. Johnson, Sara Morrison-Delap UW Cytogenetic Services (middle left and middle); R- banding (right) with chr 12 up side down - Jean Loup Huret;
Middle row: G- banding - Courtesy Jacqueline Van Den Akker (left) and Marilyn Slovak (middle left and middle); R- banding (right) with chromosome 12 up side down - Jacqueline Van Den Akker (middle right) and Jean Loup Huret (right);
Bottom row: diagram and C-banding - Jean Loup Huret.

2. Clinics and Pathology

Disease dic(9;12)(p13;p13) is most often found in B cell acute lymphocytic leukemia (B-ALL), and very rarely in T-cell acute leukemia (T-ALL), chronic lymphocytic leukemia (CLL), or non Hodgkin lymphoma (NHL).
Of 36 cases of dic(9;12) reviewed in Behrendt et al., 1995, 31 were found in precursor acute lymphoblastic leukaemias (BCP-ALL), 2 in chronic myelogenous leukemia (CML) in blast crisis (BC-CML), 1 in T-ALL, 1 in CLL, and 1 in NHL not otherwise specified.
Phenotype / cell stem origin ALLs with dic(9;12) are most often L1/L2 and CD10+, at times CIg+ ALL.
Epidemiology The PAX5 gene is altered by mutations, deletions or translocations in 30% of BCP-ALL patients and PAX5 chromosomal translocations account for 2-3% of cases (Cazzaniga et al., 2015). Dic (9;12) represents 1% of pediatric ALL (Behrendt et al., 1995)
Plotting 32 cases of B-ALL cases reviewed in Behrendt et al., 1995 and the 36 cases published by An et al., 2008 (excluding the PAX5/ SLCO1B3 case), median age was 12 years (range:1 yrs - 47 yrs; no infant case (
Clinics Moderate organomegaly. Blood data: moderate WBC.
Age at diagnosis in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).
White blood count, platelets count and Haemoglobin in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).
Survival in 30 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995). One patient died at day 11 after diagnosis from cerebral hemorrhage during induction treatment (Huret et al., 1990); all other patients were alive and well at the times of publications.
Treatment Bone marrow transplantation is not indicated, nor are high risk protocols in this leukemia with a fair prognosis.
Prognosis Complete remission is obtained in all cases; 5 years survival > 95%.

3. Cytogenetics

Note The dicentric is formed with loss of parts of 9p and 12p; therefore the ploidy is 45 chromosomes in cases where the dic(9;12) is the sole abnormality.
Cytogenetics Morphological Of 68 cases (Behrendt et al., 1995; An et al., 2008) the dic(9;12) was the sole abnormality (at least within a sub-clone) in 28 cases (41%), and was accompanied with +8 (19 cases, 28%), +21 (4 cases), del(6q) (3 cases), or -5/del(5q) (2 cases).

4. Genes involved and Proteins

Note PAX5/ETV6 fusion gene implicates two transcription factors, fundamental in hematopoiesis and in B cell development.
Gene NamePAX5 (paired box gene 5)
Location 9p13.2
Dna / Rna The PAX5 coding region extends over a genomic interval of approximately 200kb and comprises 10 exons. Two alternative transcripts have been identified, originating from alternative promotor usage, containing exon 1A or 1B. Full length mRNA is 3650 bp.
Protein PAX5 belongs to the paired box family of transcription factors, involved in a multitude of developmental processes. PAX5 was originally identified as a B-cell specific transcription factor (B-cell-specific activator protein, BSAP). Recently, it has been shown that PAX5 expression is not only continuously required for B cell lineage commitment during early B cell development but also for B lineage maintenance. Contains a paired box (DNA binding) domain, a truncated homeo domain homology region, a transactivation domain, and an inhibitory domain.
Gene NameETV6 (ets variant 6)
Location 12p13.2
Dna / Rna Alternative transcripts.
Protein Contains a HLH domain, also referred to as the pointed or sterile alpha motif domain, responsible for hetero- and homodimerization, and a ETS-DNA binding domain, responsible for sequence specific DNA-binding and protein-protein interaction; ETV6 is an ETS-related transcription factor, transcriptional repressor that binds to DNA sequence 5'- CCGGAAGT-3', It can form homodimers or heterodimers with ETV7 or FLI1.

5. Result of the chromosomal anomaly

Hybrid gene
Description In a study of dic(7;9) (n= 13), dic(9;12) (n=38), and dic(9;20) (n=59), breakpoints on 9p were found to be heterogeneous; however, all breakpoints resulted in loss of a large number of genes on 9p, including the tumor suppressor gene, CDKN2A (An et al., 2008).
5'PAX5 / 3'ETV6 transcript, no reciprocal transcript due to deletion
In the dic(9;12) cases, the breakpoints were located within intron 4 of PAX5 in 8 of 8 cases, whereas 7 were intron 2 and 1 in intron 1 of ETV6 (An et al., 2008).
Detection RT-PCR, FISH.
Fusion Protein
Description The PAX5/ETV6 chimeric transcript results in fusion of the paired box domain (PRD) of PAX5 (DNA binding domain of PAX5) to the helix-loop-helix and ETS-binding domains of ETV6 (DNA binding, dimerization and transcription regulation domains of ETV6). Of note: the putative chimeric protein contains the DNA-binding domains of both fusion partners, namely the PRD and the ETS-domain.
Expression Localisation PAX5/ETV6 localizes in the nucleus and the cytoplasm.
Oncogenesis PAX5/ETV6 acts as a transcriptional repressor. PAX5/ETV6 can multimerize and bind the PAX5-consensus sequence, determining a dominant negative activity on wild type PAX5. PAX5/ETV6 represses 56% and activates 44% of PAX5-target genes, respectively in the study by Fazio et al., 2013. On the other hand, only a few ETV6 transcriptional target genes were differentially expressed. PAX5/ETV6 determines a PAX5 haplo-insufficiency setting; the PAX5/ETV6 fusion protein could be actively responsible for the B-cell development block, mediated by the repression of physiological PAX5-activated genes (Fazio et al., 2013).
PAX5-ETV6 also interacted with wild-type ETV6, supporting the notion that the ETV6 sterile alpha domain mediates oligomerization of ETV6 and ETV6 fusion proteins (Fortschegger et al., 2014).
LCK is up-regulated by PAX5/ETV6. LCK hyper-activation, and down-regulation of its negative regulator CSK, lead to STAT5 over-phosphorylation and hyper-activation and to up-regulation of the downstream effectors, MYC and CCND2. Hyper-activation of STAT5 pathway can represent a survival signal in PAX5 translocated cells (Cazzaniga et al., 2015).

6. Bibliography

LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients.
Cazzaniga V, Bugarin C, Bardini M, Giordan M, te Kronnie G, Basso G, Biondi A, Fazio G, Cazzaniga G.
Oncotarget. 2015 Jan 30;6(3):1569-81. PubMed
PMID 25595912
Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer.
An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison CJ, Irving JA, Strefford JC.
Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17050-4. doi: 10.1073/pnas.0803494105.
PMID 18957548
Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group.
Behrendt H, Charrin C, Gibbons B, Harrison CJ, Hawkins JM, Heerema NA, Horschler-Bötel B, Huret JL, Laï JL, Lampert F
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1995 ; 9 (1) : 102-106.
PMID 7845002
The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case.
Cazzaniga G, Daniotti M, Tosi S, Giudici G, Aloisi A, Pogliani E, Kearney L, Biondi A
Cancer research. 2001 ; 61 (12) : 4666-4670.
PMID 11406533
PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5.
Fazio G, Cazzaniga V, Palmi C, Galbiati M, Giordan M, te Kronnie G, Rolink A, Biondi A, Cazzaniga G.
Leukemia. 2013 Apr;27(4):992-5. doi: 10.1038/leu.2012.281.
PMID 23090680
Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.
Fortschegger K, Anderl S, Denk D, Strehl S.
Mol Cancer Res. 2014 Apr;12(4):595-606. doi: 10.1158/1541-7786.MCR-13-0337.
PMID 24435167
Two additional cases of t dic(9:12) in acute lymphocytic leukemia (ALL): prognosis in ALL with dic(9:12).
Huret JL, Heerema NA, Brizard A, Provisor AJ, Benz-Lemoine E, Guilhot F, Savage JR, Tanzer J
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1990 ; 4 (6) : 423-425.
PMID 2193203
The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis.
Mahmoud H, Carroll AJ, Behm F, Raimondi SC, Schuster J, Borowitz M, Land V, Pullen DJ, Vietti TJ, Crist W
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1992 ; 6 (7) : 703-707.
PMID 1625489
PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13).
Strehl S, König M, Dworzak MN, Kalwak K, Haas OA
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2003 ; 17 (6) : 1121-1123.
PMID 12764378

7. Citation

This paper should be referenced as such :
Jean-Loup Huret
dic(9;12)(p13;p13) PAX5/ETV6
Atlas Genet Cytogenet Oncol Haematol. 2017;21(11):409-413.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://atlasgeneticsoncology.usal.es/classic/Anomalies/dic0912ID1065.html
History of this paper:
Huret, JL. dic(9;12)(p11-13;p11-12). Atlas Genet Cytogenet Oncol Haematol. 1997;1(1):15-15.
Huret, JL. dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol. 2003;7(3):178-180.
Strehl, S. dic(9;12)(p13;p13). Atlas Genet Cytogenet Oncol Haematol. 2004;8(2):94-96.

8. Translocations implicated (Data extracted from papers in the Atlas)

 dic(9;12)(p13;p13) PAX5/ETV6

9. External links

Mitelman databasedic(9;12)(p13;p13) [Case List]    dic(9;12)(p13;p13) [Transloc-MCList] PAX5/ETV6 [Fusion-MCList]
arrayMap (UZH-SIB Zurich)Morph ( 9811/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9837/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9975/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
arrayMap (UZH-SIB Zurich)Morph ( 9823/3) -   [auto + random 100 samples .. if exist ]   [tabulated segments]
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