t(9;12)(p24;p13) ETV6/JAK2
2014-03-01 Jean-Loup Huret Affiliation1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Clinics and Pathology
Disease
Myeloproliferative disease in transformation, myelodysplastic syndrome (MDS), B-cell acute leukemia (B-ALL), and T-cell acute leukemia (T-ALL).
Phenotype stem cell origin
One B-ALL was CD10+, the two others were not otherwise specified. The myeloproliferative disease was an atypical chronic myelogenous leukemia (a-CML).
Epidemiology
Seven patients to date: 5 male and 2 female patients. Median age was 26 years (range 1.5-80), with two children cases (one B-ALL and one T-ALL), and four cases were found in young adults (aged 25, 26, 32, 33) (Lacronique et al., 1997; Peeters et al., 1997; Najfeld et al. 2007; Zhou et al., 2012).
Prognosis
Three patients did not reach complete remission (two B-ALL and one T-ALL); one patient died 6 months after diagnosis (the a-CML case), and one patient achieved CR, relapsed; a second CR was obtained and the patient was alive 31 months after diagnosis (a B-ALL case).
Genes Involved and Proteins
Gene name
JAK2 (janus kinase 2)
Location
9p24.1
Dna rna description
24 exons.
Protein description
1132 amino acids (aa); from N-term to C-term, JAK2 contains: an interaction region with cytokine/interferon/growth hormone receptors: aa 1-239, a FERM domain: aa 37-380, a SH2 domain: aa 401-482, two protein kinase domains: aa 545-809 and 849-1124, an ATP nucleotide binding site: aa 855-863, and a loop structure: aa 1056-1078 (JAK2 kinase insertion loop). JAK homology domains are the following: JH7: aa 25-137; JH6: aa 144-284; JH5: aa 288-309; JH4: aa 322-440; JH3: aa 451-538; JH2: aa 543-824; JH1: 836-1123. Phosphotyrosines are located at aa 119, 372, 373, 523, 813, 868, 966, 972, 1007, and 1008 (Harpur et al., 1992; Saltzman et al., 1998; Lucet et al., 2006). Protein tyrosine kinase of the non-receptor type that associates with the intracellular domains of cytokine receptors; Mediates signaling transduction.
Gene name
ETV6 (ets variant 6)
Location
12p13.2
Dna rna description
9 exons; alternate splicing.
Protein description
452 amino acids. ETV6 is composed of a HLH domain responsible for hetero- and homodimerization in N-term, and an ETS domain responsible for sequence specific DNA-binding in C-term (binds to the DNA sequence 5-CCGGAAGT-3). Transcriptional regulator; tumor suppressor. Involved in bone marrow hematopoiesis.
Result of the Chromosomal Anomaly
Description
5 ETV6 - 3 JAK2. Three different hybrids have been found: fusion of ETV6 exon 4 to JAK2 exon 17 (Peeters et al., 1997), fusion of ETV6 exon 5 to JAK2 exon 17 (Lacronique et al., 1997), and fusion of ETV6 exon 5 to JAK2 exon 12 (Peeters et al., 1997).
ETV6/JAK2 fusion protein.
Description
The HLH domain of ETV6 is fused to the protein kinase domain(s), the ATP nucleotide binding, and the loop structure of JAK2; according to the different possible breakpoints, the resulting protein contains 475, 654, or 876 amino acids. Furthermore, other products result from splicing (Peeters et al., 1997). The reciprocal JAK2-ETV6 may not be expressed.
Oncogenesis
It may be speculated that the HLH domain of ETV6 induces oligomerization, resulting in constitutive activation of the kinase domain of JAK2.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 23204479 | 2012 | Modeling ETV6-JAK2-induced leukemia: insights from the zebrafish. | 26 |
| 32238402 | 2020 | The diagnostic challenges and clinical course of a myeloid/lymphoid neoplasm with eosinophilia and ZBTB20-JAK2 gene fusion presenting as B-lymphoblastic leukemia. | 25 |
| 22875628 | 2013 | Ruxolitinib as potential targeted therapy for patients with JAK2 rearrangements. | 18 |
| 32566479 | 2020 | New translocation in acute myeloid leukemia M4 eos. | 13 |
| 36068374 | 2023 | Updates on eosinophilic disorders. | 0 |
| 31482743 | 2020 | Myeloid neoplasm with eosinophilia and ETV6-JAK2 fusion. | 0 |
| 11173830 | 2000 | Fusion genes in leukemia: an emerging network. | 0 |
| 24913195 | 2014 | Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities? | 0 |
| 18297515 | 2008 | JAK and MPL mutations in myeloid malignancies. | 0 |
| 39761655 | 2025 | Direct STAT3 and STAT5 Inhibition Overcomes Treatment Resistance in a Murine-Derived in vitro Model of Acute Lymphoblastic Leukaemia Driven by ETV6::JAK2. | 0 |
| 22373549 | 2012 | Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. | 0 |
| 10449913 | 1999 | Genomic organization of human JAK2 and mutation analysis of its JH2-domain in leukemia. | 0 |
| 20507304 | 2010 | AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders. | 0 |
| 17976519 | 2007 | Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms. | 0 |
| 18476590 | 2007 | [Analysis and clinical significance of ETV6 rearrangement in myelodysplastic syndromes patients]. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 1620548 | 1992 | JAK2, a third member of the JAK family of protein tyrosine kinases. | Harpur AG et al |
| 9360930 | 1997 | A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. | Lacronique V et al |
| 16174768 | 2006 | The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor. | Lucet IS et al |
| 17976519 | 2007 | Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms. | Najfeld V 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 |
| 9618263 | 1998 | Cloning and characterization of human Jak-2 kinase: high mRNA expression in immune cells and muscle tissue. | Saltzman A et al |
| 22373549 | 2012 | Detection of ETV6 gene rearrangements in adult acute lymphoblastic leukemia. | Zhou MH et al |
Summary
Fusion gene
ETV6/JAK2 ETV6 (12p13.2) JAK2 (9p24.1) M t(9;12)(p24;p13) t(9;15;12)(p24;q15;p13)|ETV6/JAK2 ETV6 (12p13.2) JAK2 (9p24.1) TIC
Citation
Jean-Loup Huret
t(9;12)(p24;p13) ETV6/JAK2
Atlas Genet Cytogenet Oncol Haematol. 2014-03-01
Online version: http://atlasgeneticsoncology.org/haematological/1122/teaching-explorer/cancer-prone-explorer/meetings/case-report-explorer/
Historical Card
1998-02-01 t(9;12)(p24;p13) ETV6/JAK2 by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
