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

2017-01-01   Jean-Loup Huret 

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France; jean-loup.huret@chu-poitiers.fr
2.CCRI, Childrens Cancer Research Institute St. Anna Kinderkrebsforschung Kinderspitalgasse 6 A-1090, Vienna, Austria
3.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.

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 stem cell 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 (< 1yr); 5 cases ≤ 2 yrs; 22 cases between ages 2 and 10; 14 cases above 18 yrs); 72% were male patients (sex ratio: 49M/19F).

Clinics

Moderate organomegaly. Blood data: moderate WBC.
Atlas Image
Age at diagnosis in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).
Atlas Image
White blood count, platelets count and Haemoglobin in 32 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).
Atlas Image
Survival in 30 cases of B-ALL and dic(9;12)(p13;p13) - Jean Loup Huret, unpublished information (cases studied in Behrendt et al., 1995).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%.

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).

Genes Involved and Proteins

Note
PAX5/ETV6 fusion gene implicates two transcription factors, fundamental in hematopoiesis and in B cell development.
Gene name
PAX5 (paired box gene 5)
Location
9p13.2
Dna rna description
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 description
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 name
ETV6 (ets variant 6)
Location
12p13.2
Dna rna description
Alternative transcripts.
Protein description
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.

Result of the Chromosomal Anomaly

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).
5PAX5 / 3ETV6 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 protocole

RT-PCR, FISH.
Atlas Image

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).

Highly cited references

Pubmed IDYearTitleCitations
282199272017Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia.16
127643782003PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13).16
244351672014Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.13
230906802013PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5.10
223735492012Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia.9
255959122015LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients.8
297867572018Copy number abnormality of acute lymphoblastic leukemia cell lines based on their genetic subtypes.3
342091962021Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols.2
295204342018A patient with B-cell acute lymphoblastic leukemia with PAX5-ETV6 rearrangement with dic(9;12)(p13;p13) identified by chromosomal microarray.0

Bibliography

Pubmed IDLast YearTitleAuthors
255959122015LCK over-expression drives STAT5 oncogenic signaling in PAX5 translocated BCP-ALL patients.Cazzaniga V et al
189575482008Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer.An Q et al
78450021995Dicentric (9;12) in acute lymphocytic leukemia and other hematological malignancies: report from a dic(9;12) study group.Behrendt H et al
114065332001The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case.Cazzaniga G et al
230906802013PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5.Fazio G et al
244351672014Functional heterogeneity of PAX5 chimeras reveals insight for leukemia development.Fortschegger K et al
21932031990Two additional cases of t dic(9:12) in acute lymphocytic leukemia (ALL): prognosis in ALL with dic(9:12).Huret JL et al
16254891992The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis.Mahmoud H et al
127643782003PAX5/ETV6 fusion defines cytogenetic entity dic(9;12)(p13;p13).Strehl S et al

Summary

Fusion gene

PAX5/ETV6

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.
Atlas Image
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.

Citation

Jean-Loup Huret

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

Atlas Genet Cytogenet Oncol Haematol. 2017-01-01

Online version: http://atlasgeneticsoncology.org/haematological/1065/dic(9;12)(p13;p13)

Historical Card

2004-01-01 dic(9;12)(p13;p13) PAX5/ETV6 by  Sabine Strehl 

CCRI, Childrens Cancer Research Institute St. Anna Kinderkrebsforschung Kinderspitalgasse 6 A-1090, Vienna, Austria

2003-06-01 dic(9;12)(p13;p13) PAX5/ETV6 by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France; jean-loup.huret@chu-poitiers.fr

1997-08-01 dic(9;12)(p13;p13) PAX5/ETV6 by  Jean-Loup Huret 

Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France; jean-loup.huret@chu-poitiers.fr

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