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t(5;9)(q14.1;p24) SSBP2/JAK2

Written2014-05Elizabeth A Morgan, Paola Dal Cin
Department of Pathology, Brigham, Women's Hospital, Boston, MA, USA

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
ICD-Morpho 9811/3 B lymphoblastic leukaemia/lymphoma, NOS
Atlas_Id 1680
Other namesSSBP2-JAK2 fusion

Clinics and Pathology

Disease B-lymphoblastic leukemia/lymphoma
Phenotype / cell stem 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 5'JAK2 hybridization signal on der(5), the 3'JAK2 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
Location 5q14.1
Dna / Rna 17 exons.
Protein Single-stranded DNA-binding complex; plays role in the maintenance of genome stability.
Gene Name JAK2
Location 9p24
Dna / Rna 24 exons.
Protein Tyrosine kinase; cytokine receptor signaling.

Result of the chromosomal anomaly

Hybrid gene
Description 5'SSBP2-3'JAK2.
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).
  
Fusion Protein
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.
  

To be noted

JAK2 fusion proteins have been described in several hematopoietic neoplasms including acute leukemias and myeloproliferative neoplasms. The fusion partners reported in B-lineage acute lymphoblastic leukemia (ALL) include ETV6 (Peeters et al., 1997), PCM1 (Reiter et al., 2005), PAX5 (Nebral et al., 2009), BCR and STRN3 (Roberts et al., 2012). It is thought that these fusions result in constitutive JAK2 tyrosine kinase activity, and it is predicted that patients with B-ALL exhibiting one of these fusions may respond to JAK2 inhibitors (Lacronique et al., 1997; Roberts et al., 2012). This is clinically relevant given that at least the PAX5-JAK2, BCR-JAK2 and STRN3-JAK2 fusions have been associated with a group of high-risk B-lineage ALLs known as BCR-ABL1 negative ALL or "Ph-like ALL", which are characterized by a gene expression profile similar to BCR-ABL1-positive ALL, an alteration of IKZF1, and poor prognosis (Roberts et al., 2012). The translocation described herein describes an additional JAK2 fusion protein in B-lineage ALL (SSBP2-JAK2) (Poitras et al., 2008).

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

A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia.
Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffe M, Berthou C, Lessard M, Berger R, Ghysdael J, Bernard OA.
Science. 1997 Nov 14;278(5341):1309-12.
PMID 9360930
 
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
 
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, Raynaud SD, Cools J, Wlodarska I, Grosgeorge J, Philip P, Monpoux F, Van Rompaey L, Baens M, Van den Berghe H, Marynen P.
Blood. 1997 Oct 1;90(7):2535-40.
PMID 9326218
 
Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia.
Poitras JL, Dal Cin P, Aster JC, Deangelo DJ, Morton CC.
Genes Chromosomes Cancer. 2008 Oct;47(10):884-9. doi: 10.1002/gcc.20585.
PMID 18618714
 
The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2.
Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B, Berger U, Telford N, Aruliah S, Yin JA, Vanstraelen D, Barker HF, Taylor PC, O'Driscoll A, Benedetti F, Rudolph C, Kolb HJ, Hochhaus A, Hehlmann R, Chase A, Cross NC.
Cancer Res. 2005 Apr 1;65(7):2662-7.
PMID 15805263
 
Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.
Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, Payne-Turner D, Churchman ML, Harvey RC, Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, Mungall K, Birol I, Edmonson MN, Hu Y, Buetow KE, Chen IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia-Manero G, Larsen E, Shah NP, Devidas M, Reaman G, Smith M, Paugh SW, Evans WE, Grupp SA, Jeha S, Pui CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra MA, Mullighan CG.
Cancer Cell. 2012 Aug 14;22(2):153-66. doi: 10.1016/j.ccr.2012.06.005.
PMID 22897847
 

Citation

This paper should be referenced as such :
EA Morgan, Cin P Dal
t(5;9)(q14.1;p24) SSBP2/JAK2
Atlas Genet Cytogenet Oncol Haematol. 2015;19(1):59-61.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0509q14p24ID1680.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(5;9)(q14.1;p24) SSBP2/JAK2

External links

SSBP2 (5q14.1) JAK2 (9p24.1)

SSBP2 (5q14.1) JAK2 (9p24.1)

SSBP2 (5q14.1) JAK2 (9p24.1)

Mitelman databaset(5;9)(q14.1;p24) [Case List]    t(5;9)(q14.1;p24) [Association List] Mitelman database (CGAP - NCBI)
arrayMapTopo ( C42) Morph ( 9811/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionSSBP2/JAK2 SSBP2 (5q14.1) JAK2 (9p24.1)   [fusion1045]   [fusion1046]   [fusion1047]   [fusion1048]  
Mitelman databaseSSBP2/JAK2 [MCList]  SSBP2 (5q14.1) JAK2 (9p24.1)
TICdbSSBP2/JAK2  SSBP2 (5q14.1) JAK2 (9p24.1)
 
Other databaseCOSMIC
Disease databaset(5;9)(q14.1;p24) SSBP2/JAK2
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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