The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene

Abstract

Several tyrosine kinase genes are involved in chromosomal translocations in chronic myeloproliferative disorders, but there are still uncharacterized translocations in some cases. We report two such cases corresponding to atypical chronic myeloid leukaemia with a t(8;9)(p22;p24) translocation. By fluorescence in situ hybridisation (FISH) on the corresponding metaphases with a bacterial artificial chromosome probe encompassing the janus kinase 2 (JAK2) gene at 9p24, we observed a split for both patients, suggesting that this gene was rearranged. The locus at 8p22 contains different candidate genes including the pericentriolar material 1 gene (PCM1), already implicated in reciprocal translocations. The rearrangement of the PCM1 gene was demonstrated by FISH, for both patients. By RT-PCR, we confirmed the fusion of 3 0 part of JAK2 with the 5 0 part of PCM1. Sequence analysis of the chimeric PCM1-JAK2 mRNA suggests that the putative protein displays the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2. This new translocation identifies JAK2 as a possible therapeutic target for compounds with antityrosine kinase activity.

Fusion tyrosine kinases: a result and cause of genomic instability

“…ZNF198/FGFR1 is formed by the fusion of the N-terminal of ZNF198 to the entire catalytic domain of FGFR1. PCM1/JAK2 results from t(8;9) translocation observed in atypical chronic myeloid leukemia/chronic eosinophilic leukemia, secondary AML and pre-B-cell ALL (Bousquet et al, 2005;Reiter et al, 2005).…”

Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

“…50 The chimeric oncoprotein results from the t(8;9)(p22;p24) chromosomal translocation and may have pleiotropic clinical presentations, including atypical CML, AML, acute B-and T-cell lymphoblastic leukemias, often with peripheral eosinophilia. [50][51][52][53][54] The clinical course of the PCM1-JAK2 cases reported to date appears to be more aggressive than the JAK2 V617F-associated chronic MPDs. JAK2 inhibitors currently in phase I testing exhibit potential for treating these neoplasms characterized by constitutive JAK2 activation.…”

Recurrent numerical aberrations of JAK2 and deregulation of the JAK2-STAT cascade in lymphomas

“…[2][3][4] Recently, translocations involving the JAK2 locus such as t(9;12)(p24;p23), t(8;9)(p24;q11.2), t(3;9) (q21;p24) and t(8;9)(p22;p24) were suggested to be of oncogenic importance in various hematological neoplasms, such as acute lymphoblastic and myelogenous leukemias, atypical chronic myeloid leukemias, myelodysplastic/myeloproliferative diseases and peripheral T-cell lymphomas. [5][6][7][8][9][10][11] Gains of JAK2 gene dosage, particularly due to trisomy 9p24, which is recurrent in classical Hodgkin's lymphoma …”