t(5;9)(q14.1;p24) SSBP2/JAK2
2014-05-01 Elizabeth A Morgan , Paola Dal Cin, PhD Affiliation1.Department of Pathology, Brigham, Womens Hospital, Boston, MA, USA
2.Department of Pathology, Brigham, Women s Hospital, Boston, MA, USA
Clinics and Pathology
Disease
B-lymphoblastic leukemia/lymphoma
Phenotype stem cell origin
CD45+(dim), TdT+, CD34+(subset), HLA-DR+, CD19+, CD10+, and CD20+(variable) with weak aberrant expression of the myeloid markers CD13 and CD33; no expression of surface immunoglobulin, T lymphoid, and other myeloid and monocytic markers.
Epidemiology
One reported case; 39-year-old male presenting with a white blood cell count of 400x109/L with 98% blasts (Poitras et al., 2008).
Treatment
Prednisone, vincristine, doxorubicin, asparaginase, and high-dose methotrexate; achieved complete remission after 30 days of cytoreductive chemotherapy; also received prophylactic intrathecal chemotherapy and cranial radiation.
Prognosis
Rapid systemic relapse; 8 months after initial diagnosis the patient died from progressive disease.
Cytogenetics
Note
t(5;9) detected in 19 of 20 GTG-banded metaphase cells analyzed from a 24-hr unstimulated bone marrow culture.
a). Partial GTG-banded karyotypes showing the t(5;9)(q14.1;p24.1). b). Partial FISH analysis showing the 5JAK2 hybridization signal on der(5), the 3JAK2 hybridization signal on der(9) and an intact JAK2 hybridization signal on the normal chromosome 9.
Cytogenetics molecular
The breakpoint on chromosome 9p was found to be distal to band p23 by FISH mapping on abnormal metaphase. The breakpoint was found to reside within the JAK2 locus by hybridizing a BAC spanning the JAK2 gene (RP11-927h16; nucleotides 4965192-5138016), which produced signals on both der(9) and der(5) chromosomes. Additional FISH mapping localized the chromosome 5 breakpoint to a 57.5 kb interval at 5q14.1 spanning SSBP2, with RP11-120L4 (nucleotides 80698679-80848640) and RP11-147O19 (nucleotides 80861153-81023195) flanking the breakpoint; the presence of the SSBP2-JAK2 transcript was confirmed by RT-PCR.
Additional anomalies
With disease progression, a subsequent sample revealed additional chromosome aberrations: 46,XY,t(5;9)(q14.1;p24.1) [cp10]/46,idem, t(1;13)(p22;q32), t(15;20)(q15;q13)[3]/46,idem,t(1;3)(p36;p21),del(12)(q12q13)[cp7].
Genes Involved and Proteins
Gene name
SSBP2 (single stranded DNA binding protein 2)
Location
5q14.1
Dna rna description
17 exons.
Protein description
Single-stranded DNA-binding complex; plays role in the maintenance of genome stability.
Gene name
JAK2 (janus kinase 2)
Location
9p24.1
Dna rna description
24 exons.
Protein description
Tyrosine kinase; cytokine receptor signaling.
Result of the Chromosomal Anomaly
Description
5SSBP2-3JAK2.
Transcript
RT-PCR using the forward primer in exon 3 of SSBP2 and the reverse primer in exon 12 of JAK2 yielded three discrete products of 465 bp, 375 bp, and 290 bp; sequencing revealed that each contained the same 3 JAK2 sequences (exon 11 and downstream 3 sequence), but different joining 5 SSBP2 sequences (junction occurred at the 3 end of SSBP2 exons 5, 4, and 3, respectively termed T1-T3).
Description
It is predicted that T1 and T2, which are both in-frame, will encode SSBP2-JAK2 fusion proteins containing the SSBP2 Lissencephaly type I-like homology (LisH) motif as well as the JH2 and JH1 domains of JAK2; the T3 fusion is out of frame and may encode a truncated SSBP2 protein with a COOH-terminal deletion of the proline-rich, glycine-rich, and downstream regions.
Oncogenesis
Other JAK2 fusions with other partners genes PCM1 (8p22), BCR (22q11.2) and ETV6 (12p13) lead to dimerization of adjacent, receptor-associated JAKs, and ensuing auto- and trans-phosphorylation causing constitutive kinase activation (Lacronique et al., 1997); it is predicted that the LisH (Lissencephaly type I-like homology) motif in SSBP2 may permit a similar mechanism of JAK2 activation.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 18618714 | 2008 | Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 9360930 | 1997 | A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. | Lacronique V et al |
| 19020546 | 2009 | Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. | Nebral K et al |
| 9326218 | 1997 | Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. | Peeters P et al |
| 18618714 | 2008 | Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. | Poitras JL et al |
| 15805263 | 2005 | The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. | Reiter A et al |
| 22897847 | 2012 | Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. | Roberts KG et al |
Summary
Fusion gene
SSBP2/JAK2 SSBP2 (5q14.1) JAK2 (9p24.1) COF 1045 1046 1047 1048|SSBP2/JAK2 SSBP2 (5q14.1) JAK2 (9p24.1) M t(5;9)(q14;p24)|SSBP2/JAK2 SSBP2 (5q14.1) JAK2 (9p24.1) TIC
Citation
Elizabeth A Morgan ; Paola Dal Cin, PhD
t(5;9)(q14.1;p24) SSBP2/JAK2
Atlas Genet Cytogenet Oncol Haematol. 2014-05-01
Online version: http://atlasgeneticsoncology.org/haematological/1680/t(5
