C loning and functional characterization of a large number of chromosomal translocations revealed that aberrant activation of protein kinases is a key event for expansion of the malignant clone in chronic myeloproliferative disorders, as well as in acute leukemia. The best known example is t(9;22)(q34;q11), leading to the expression of the BCR-ABL1 (BCR-ABL) tyrosine kinase fusion associated with chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL). In 1997, two studies reported that the JAK2 gene on the short arm of chromosome 9p24 encoding for just another cytoplasmic protein tyrosine kinase is involved in rare chromosomal translocations resulting in fusions to the ETS-family member ETV6 (also known as TEL). Interestingly, particular breakpoints were found resulting in variant fusion proteins that were associated with different disease phenotypes. Peeters and colleagues cloned a t(9;12)(p24;p13) from a patient with early pre-B cell acute lymphoblastic leukemia (ALL) leading to a fusion of exon 4 of ETV6 to exon 17 of JAK2 (ETV6-JAK2, 4-17). In addition, they identified a t(9;15;12)(p24;q15;p13) in a patient with atypical CML in a transformation that fused exon 5 of ETV6 to exon 12 of JAK2 (ETV6-JAK2, 5-12).1 In parallel, Lacronique and colleagues cloned a t(9;12)(p24;p13) from blasts from a childhood T-cell ALL patient leading to a fusion of ETV6 exon 5 to JAK2 exon 19 containing only the JH1 tyrosine kinase domain (ETV6-JAK2, 5-19).2 Since their original description, very few additional cases of hematologic malignancies with ETV6-JAK2 have been reported. 3 Later, additional translocations involving the JAK2 gene were identified, such as t(9;22)(q34;q11.2) leading to a BCR-JAK2 fusion, t(8;9)(p22;p24) leading to a fusion to the pericentrilar material 1 (PCM1) gene, or t(4;9)(q21;p24) fusing JAK2 to the SEC31A gene. [4][5][6] Interestingly, in all of the PCM1-JAK2 positive cases reported so far, large parts of JAK2 (exon 9) were included and associated with a wide disease phenotype spectrum, including atypical CML, myelodysplasia/-proliferation with erythroid hyperplasia, or T-cell lymphoma. To address the biological activity of an ETV6-JAK2 fusion, several groups over-expressed the three fusion variants in IL-3 dependent murine Ba/F3 cells. Expression of all ETV6-JAK2 variants rendered Ba/F3 cells IL-3-independent with similar efficacy. Transformation of the cells by ETV6-JAK2 expression was associated with constitutive activation of the signal transducers and activators of transcription (STATs), predominantly of STAT5, but also STAT1 and STAT3, and expression of several putative STAT targets such as oncostatin M, CIS or PIM1.
8-10To model ETV6-JAK2 disease in vivo, we transplanted bone marrow cells with retroviral expression of the 5-19 fusion variant in lethally irradiated mice. All the mice developed an aggressive lethal mixed T-cell lympho-and myeloproliferative disease after a latency of 5-10 weeks. 8 Similarly, transgenic mice expressing the ETV6-JAK2 (5-19) variant from an SRα ...