The t(8;9)(p22;p24) Is a Recurrent Abnormality in Chronic and Acute Leukemia that Fuses PCM1 to JAK2

Abstract

We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2-PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy. (Cancer Res 2005; 65(7): 2662-7)

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

“…49 In 2005, the PCM1-JAK2 fusion was identified as a second recurrent molecular abnormality, which results in dysregulation of JAK2 tyrosine kinase activity due to oligomerization mediated by the coiled-coil domains of PCM1. 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.…”

“…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.…”

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).…”

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 …”