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Monika Prochorecsobieszek - One of the best experts on this subject based on the ideXlab platform.
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t 8 9 p22 p24 PCM1 jak2 activates socs2 and socs3 via stat5
PLOS ONE, 2013Co-Authors: Stefan Ehrentraut, Stefan Nagel, Michaela Scherr, Hilmar Quentmeier, Robert Geffers, Monika Prochorecsobieszek, Bjorn Schneider, Maren Kaufmann, Corinna Meyer, Rhett P KetterlingAbstract:Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B - the first JAK2–translocation leukemia/lymphoma cell lines described - display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.
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t 8 9 p22 p24 PCM1 jak2 activates socs2 and socs3 via stat5
Blood, 2012Co-Authors: Stefan Ehrentraut, Stefan Nagel, Michaela Scherr, Bjoern Schneider, Hilmar Quentmeier, Robert Geffers, Monika Prochorecsobieszek, Rhett P Ketterling, Ryan A Knudson, Andrew L FeldmanAbstract:Abstract 1567 Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they are believed to promote JAK2-oligomerization and autonomous signalling although the underlying mechanisms remain unclear. Affected entities are candidates for therapy with JAK2 signalling inhibitors. Among 200 peripheral T-cell lymphomas surveyed, we identified only two with JAK2 amplification and none with JAK2 translocations, confirming their rarity in T-cell neoplasias. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in cell lines established at indolent and aggressive phases of a cutaneous T-cell lymphoma. To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 genes most upregulated in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive phase cells, was partially restored by PCM1-JAK2 knockdown. Activation of the tumor suppressor SOCS3 by PCM1-JAK2 may follow structural alteration of JAK2 affecting the ternary complex it forms with SOCS3 and receptor proteins. Treatment with JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive mimicked knockdown results, highlighting JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5 as reported for JAK2V617F or ETV6/TEL-JAK2, thus extending the paradigm of STAT5 activation by JAK2 alterations in hematopoietic malignancies. MAC-1/2A/2B are the first JAK2– translocation cell line models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements. Disclosures: No relevant conflicts of interest to declare.
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chronic eosinophilic leukemia with erythroblastic proliferation and the rare translocation t 8 9 p22 p24 with PCM1 jak2 fusion gene a distinct clinical pathological and genetic entity with potential treatment target
Leukemia & Lymphoma, 2012Co-Authors: Monika Prochorecsobieszek, Barbara Nasilowskaadamska, Katarzyna Borg, Izabella Kopec, Kinga Koszakrzewska, Przemyslaw Juszczynski, Krzysztof WarzochaAbstract:Myeloid and lymphoid neoplasms resulting from t(8;9)(p21-23;p23-24) involving pericentriolar material 1 (PCM1) gene and the janus-activated kinase 2 (JAK2) gene are very rare disorders. Most patients present with myeloproliferative neoplasms (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS-MPN) accompanied by eosinophilia and myelofibrosis. Their clinical course is more aggressive than other MPN and MDS-MPN with tendency to transformation to acute myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1-JAK2 fusion leads to constitutive activation of JAK2. Such patients might be candidates for target therapies with JAK2 inhibitors. We report a patient with chronic eosinophilic leukemia, not otherwise specified with erythroblastic proliferation of unclear significance and the translocation (8;9) (p22;p24) with PCM1-JAK2 fusion gene. The presence of characteristic genetic aberration with potential terapeutic target tends to separate this disease as a distinct clinical, histopathological and genetic entity.
Takashi Toda - One of the best experts on this subject based on the ideXlab platform.
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a non canonical function of plk4 in centriolar satellite integrity and ciliogenesis through PCM1 phosphorylation
EMBO Reports, 2016Co-Authors: Ambrosius P. Snijders, Akiko Hori, Karin Barnouin, Takashi TodaAbstract:Centrioles are the major constituents of the animal centrosome, in which Plk4 kinase serves as a master regulator of the duplication cycle. Many eukaryotes also contain numerous peripheral particles known as centriolar satellites. While centriolar satellites aid centriole assembly and primary cilium formation, it is unknown whether Plk4 plays any regulatory roles in centriolar satellite integrity. Here we show that Plk4 is a critical determinant of centriolar satellite organisation. Plk4 depletion leads to the dispersion of centriolar satellites and perturbed ciliogenesis. Plk4 interacts with the satellite component PCM1, and its kinase activity is required for phosphorylation of the conserved S372. The nonphosphorylatable PCM1 mutant recapitulates phenotypes of Plk4 depletion, while the phosphomimetic mutant partially rescues the dispersed centriolar satellite patterns and ciliogenesis in cells depleted of PCM1. We show that S372 phosphorylation occurs during the G1 phase of the cell cycle and is important for PCM1 dimerisation and interaction with other satellite components. Our findings reveal that Plk4 is required for centriolar satellite function, which may underlie the ciliogenesis defects caused by Plk4 dysfunction.
Krzysztof Warzocha - One of the best experts on this subject based on the ideXlab platform.
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chronic eosinophilic leukemia with erythroblastic proliferation and the rare translocation t 8 9 p22 p24 with PCM1 jak2 fusion gene a distinct clinical pathological and genetic entity with potential treatment target
Leukemia & Lymphoma, 2012Co-Authors: Monika Prochorecsobieszek, Barbara Nasilowskaadamska, Katarzyna Borg, Izabella Kopec, Kinga Koszakrzewska, Przemyslaw Juszczynski, Krzysztof WarzochaAbstract:Myeloid and lymphoid neoplasms resulting from t(8;9)(p21-23;p23-24) involving pericentriolar material 1 (PCM1) gene and the janus-activated kinase 2 (JAK2) gene are very rare disorders. Most patients present with myeloproliferative neoplasms (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS-MPN) accompanied by eosinophilia and myelofibrosis. Their clinical course is more aggressive than other MPN and MDS-MPN with tendency to transformation to acute myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1-JAK2 fusion leads to constitutive activation of JAK2. Such patients might be candidates for target therapies with JAK2 inhibitors. We report a patient with chronic eosinophilic leukemia, not otherwise specified with erythroblastic proliferation of unclear significance and the translocation (8;9) (p22;p24) with PCM1-JAK2 fusion gene. The presence of characteristic genetic aberration with potential terapeutic target tends to separate this disease as a distinct clinical, histopathological and genetic entity.
Robert Kralovics - One of the best experts on this subject based on the ideXlab platform.
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efficacy of ruxolitinib in chronic eosinophilic leukemia associated with t 8 9 p22 p24 and PCM1 jak2 fusion gene
Blood, 2012Co-Authors: Ilaria Casetti, Elisa Rumi, Jelena D Milosevic, Irene Dambruoso, Daniela Pietra, Emanuela Boveri, Marina Boni, Paolo Bernasconi, Francesco Passamonti, Robert KralovicsAbstract:Abstract 2833 The Janus kinase 2 ( JAK2 ) gene is activated by point mutation (V617F) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN), playing an important role in their pathogenesis. This has led to clinical trials on the use of JAK2 inhibitors in the treatment of MPN, and to the recent approval of ruxolitinib for treatment of primary myelofibrosis. JAK2 may also be activated by translocation and fusion with another gene. The t(8;9) (p21–23;p23–24), found in atypical myeloid and lymphoid neoplasms, fuses JAK2 with the Pericentriolar Material 1 ( PCM1 ) gene, activating JAK2 . A 31-year-old female patient was referred to our Department because of splenomegaly (12 cm below costal margin), anemia (11.5 g/dL), leukocytosis (WBC 21.6 × 10 9 /L) with eosinophilia (eosinophils 3.5 × 10 9 /L ), and thrombocytopenia (107 × 10 9 /L ). The bone marrow biopsy was hypercellular (95%), and showed eosinophil proliferation and fibrosis. Studies of X-chromosome inactivation pattern demonstrated clonal hematopoiesis, while cytogenetic analysis revealed t(8;9)(p22;p24). There was no evidence of BCR-ABL1 fusion gene nor of PDGFRA or PDGFRB rearrangements, and a diagnosis of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) was made. The candidate genes for fusion were PCM1 on chromosome 8p22 and JAK2 on chromosome 9p24. Fluorescence in situ hybridization (FISH) on bone marrow cells with probes for PCM1 and JAK2 revealed the presence of two fused signals on der(8) and der(9), indicating the presence of a PCM1-JAK2 rearrangement. The presence of chimeric PCM1-JAK2 fusion transcript was confirmed by reverse transcription PCR (RT-PCR) in RNA from circulating granulocytes. Sanger sequencing was performed to define the fusion junctions, and this showed an in-frame fusion between PCM1 exon 36 and JAK2 exon 9. The fusion protein retains the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2: this likely facilitates oligomerization of the PCM1-JAK2 chimera resulting in a constitutive activation of JAK2. The clinical course of patients with PCM1-JAK2 -fusion-associated neoplasms is generally poor, and allogeneic stem cell transplantation represents the only curative treatment. Unfortunately our patient did not have a compatible stem cell donor. A SNP array evaluation did not detect any additional chromosomal aberration, and the PCM1-JAK2 fusion emerged as the unique genetic lesion. We therefore considered a treatment with a JAK2 inhibitor, and more specifically a compassionate use of ruxolitinib. Following approval by the local Ethics Committee and written informed consent, in July 2011 the patient started ruxolitinib at a dose of 15 mg BID. As of July 2012, this treatment is still ongoing without any adverse effect. The patient obtained a complete clinical remission with regression of anemia, leukocytosis, eosinophilia, splenomegaly and marrow fibrosis, and with restoration of polyclonal hematopoiesis. The cytogenetic response was assessed on bone marrow at 3, 6, and 12 months. The percentage of metaphases with t(8;9) showed a progressive decrease from baseline (80%) to the 12th month of treatment (30%). Similarly, FISH with the commercial probe ON JAK2 (9p24) Break (Kreatech Diagnostics, Amsterdam, The Netherlands), optimized to detect translocations involving JAK2 at region 9p24, revealed a progressive reduction in the proportion of rearranged nuclei. To monitor the amount of fusion transcript, we used quantitative PCR analysis for the PCM1-JAK2 rearrangement in RNA samples collected from granulocytes at 3, 6, 9 and 12 months. Quantitative PCR analysis showed an early reduction in the level of PCM1-JAK2 fusion transcript, followed by a plateau at about 20% of the baseline value. In conclusion, the identification of the PCM1-JAK2 fusion gene in our patient with CEL provided a molecular target for treatment with the oral JAK2 inhibitor ruxolitinib, which allowed a complete clinical remission and a considerable reduction in the PCM1-JAK2 clone size. As complete hematologic remissions are unlikely in MPN patients treated with ruxolitinib, our case may suggest that ruxolitinib is more effective in patients in whom JAK2 is activated by translocation than in those in whom it is activated by point mutation. Finally, since PCM1-JAK2 -fusion-associated neoplasms have a poor prognosis, clinical trials on the use of ruxolitinib should be considered in patients with these disorders. Disclosures: Off Label Use: Ruxolitinib for treatment of PCM1-JAK2-fusion-associated chronic eosinophilic leukemia.
Danny Vanstraelen - One of the best experts on this subject based on the ideXlab platform.
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the t 8 9 p22 p24 is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to jak2
Cancer Research, 2005Co-Authors: Andreas Reiter, Christoph Walz, Ann E Watmore, Claudia Schoch, Ilona Blau, Brigitte Schlegelberger, U Berger, Nicholas Telford, Shilani Aruliah, Danny VanstraelenAbstract: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.
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recurrent fusion of PCM1 to jak2 in atypical chronic myeloid leukemia and acute leukemia associated with the t 8 9 p21 22 p23 24
Blood, 2004Co-Authors: Andreas Reiter, Christoph Walz, Ann E Watmore, Claudia Schoch, Ilona Blau, Nicholas Telford, Shilani Aruliah, Danny Vanstraelen, Helen C Barker, Peter M TaylorAbstract:We have identified a novel, recurrent t(8;9)(p21–22;p23–24) in six patients with diverse hematological malignancies: atypical CML (n=4), secondary AML following idiopathic myelofibrosis (n=1) and pre B-ALL (n=1). Because of the involvement of several different tyrosine kinases in atypical CML, we focused our analysis on this class of gene. Initial FISH studies of one patient indicated that the janus kinase 2 gene (JAK2), located at 9p24, was disrupted. RACE-PCR was then used to identify the 8p21 partner gene as PCM1, a large centrosomal protein that contains multiple coiled-coil domains. RT-PCR and FISH analysis confirmed the fusion in this case, and also identified PCM1-JAK2 in the five other t(8;9) patients (RT-PCR and FISH, n=4; RT-PCR only, n=1; FISH only, n=1). Four different types of in-frame mRNA junction were identified, 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 could not be amplified in any patient. Clinically, 4 patients displayed CML-like hyperplasia with variable degrees of myelofibrosis and eosinophilia. Similar to typical CML, the clinical course of these patients was variable: one is alive 11 months after allogeneic stem cell transplantation, one transformed to acute leukemia 5 years after diagnosis, one died 4 days after presentation and one achieved a major cytogenetic response with interferon but died due to neurodegenerative disease and pneumonia at 7.5 years. Of the two remaining patients, one presented with secondary AML following idiopathic myelofibrosis and remains in remission 15 years after diagnosis following intensive chemotherapy and maintenance with interferon. The final patient died shortly after induction therapy for pre B-ALL. In conclusion, PCM1-JAK2 is a novel recurrent fusion gene in hematological malignancies that is likely to deregulate hemopoiesis in a manner similar to BCR-ABL. Patients with PCM1-JAK2 disease are attractive targets for signal transduction therapy.