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.

ALLs with dic(9;12) are most often L1/L2 and CD10+, at times CIg+ ALL.

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).

Moderate organomegaly. Blood data: moderate WBC.

Bone marrow transplantation is not indicated, nor are high risk protocols in this leukemia with a fair prognosis.

Complete remission is obtained in all cases; 5 years survival > 95%.

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.

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).

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).

RT-PCR, FISH.

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.

PAX5/ETV6 localizes in the nucleus and the cytoplasm.

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).

PAX5/ETV6

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.