PCM1-JAK2 Fusion Research Articles

PCM1-JAK2Fusion Tyrosine Kinase Gene-Related Neoplasia: A Systematic Review of the Clinical Literature

BackgroundThis review summarizes the case studies of PCM1-JAK2 fusion tyrosine kinase gene-related neoplasia. Recommended treatment includes JAK2 inhibitors and hematologic stem cell transplantation (HSCT), although the small number of patients has limited study of their efficacy. Herein, we present all available cases in the current searchable literature with their demographics, diagnoses, treatments, and outcomes.MethodsPubMed, ScienceDirect, Publons, the Cochrane Library, and Google were searched with the following terms: PCM1-JAK2, ruxolitinib and myeloid/lymphoid.ResultsSixty-six patients (mean age = 50, 77% male) had an initial diagnosis of myeloproliferative neoplasm (MPN) in 40, acute leukemia in 21 and T-cell cutaneous lymphoma in 5. Thirty-five patients (53%) had completed 5-year follow-up. The 5-year survival for the MPN, acute myelogenous leukemia (AML), acute lymphocytic leukemia, and lymphoma groups are 62.7, 14.9%, 40.0%, and 100%, respectively. Too few patients have been treated with ruxolitinib to draw conclusions regarding its effect on survival while the 5-year survival for MPN patients with or without HSCT was 80.2% (40.3%-94.8%) versus 51.5% (22.3%-74.6%), respectively. The T-cell cutaneous lymphoma patients have all survived at least 7 years.ConclusionThis rare condition may be increasingly detected with wider use of genomics. Ruxolitinib can yield hematologic and molecular remissions. However, HSCT is, at this time, the only potentially curative treatment. Useful prognostic markers are needed to determine appropriate timing for HSCT in patients with MPN. Patients presenting with acute leukemia have a poor prognosis.

Treatment of PCM1-JAK2 Fusion Tyrosine Kinase Gene-Related Acute Lymphoblastic Leukemia with Stem Cell Transplantation

PCM1-JAK2 fusion mutations are rare variants that activate a tyrosine kinase leading to a variety of neoplasms that can involve any hematologic cell line. They most often present as myelodysplasia (MPD) and can demonstrate prominent eosinophilia and/or erythrodysplasia. Transformation to acute leukemia is often seen, as is de novo leukemia. Lymphomas have also been reported. The diagnosis can often be made with routine cytogenetic analysis but specific probes and detailed next generation sequencing may be necessary. JAK2 inhibitors are active in MPD as is stem cell transplantation. Transplantation has occasionally been successful in leukemic phase as well. The current case highlights both the difficulties in diagnosis as well as the second successful treatment of MPD, transformed into acute lymphoblastic leukemia.

TBL1XR1-JAK2: a novel fusion in a pediatric T cell acute lymphoblastic leukemia patient with increased absolute eosinophil count

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) with any JAK2 gene fusion is rarely reported. Here, we report a case of T-ALL with a novel TBL1XR1-JAK2 gene fusion in a 5-year-old boy. His lab showed a high white blood cell count, mild anemia, moderate thrombocytopenia, and concurrently increased eosinophils (absolute eosinophil count: 4 × 10^9/L). Peripheral blood and bone marrow aspirate smears showed > 90% mononucleated blasts. Flow cytometry on peripheral blood revealed a large blast population positive for CD2, surface CD3 (< 25%), CD10 (50%), CD5, CD7, CD4, CD8, TdT, CD1a (60%), and CD45. Conventional karyotype analysis showed t(3;9)(q26;p24) and t(11;14)(p13;q11.2)/TCRD-LMO2. Next-generation sequencing (NGS) identified a novel TBL1XR1-JAK2 gene fusion in a sequencing depth of 180 × by RNAseq, FBXW7 R465H mutation, and loss of exons 2–3 of CDKN2A/B by DNAseq. Follow-up bone marrow aspirate on day-28 post-induction therapy revealed no morphologic evidence of residual leukemia. We believe that the TBL1XR1-JAK2 fusion may behave in a similar functional manner to the PCM1-JAK2 fusion gene and constitutes a new variant of this family and a potential target of tyrosine kinase inhibitor (TKI) therapy.

Hematopoietic neoplasms with 9p24/JAK2 rearrangement: a multicenter study

The purpose of this study is to examine hematopoietic neoplasms with 9p24/JAK2 rearrangement including neoplasms associated with t(8;9)(p22;p24)/PCM1-JAK2 fusion neoplasm as well as cases with translocations involving 9p24/JAK2 and other partner genes. From seven large medical centers, we identified ten patients with t(8;9)(p22;p24) /PCM1-JAK2 and 3 with t(9p24;v)/JAK2 at diagnosis. Majority of the cases showed myeloproliferative neoplasm (MPN) associated features (n = 7) characterized by variable degrees of eosinophilia, myelofibrosis, frequent proliferations of early erythroblasts in bone marrow and extramedullary sites, and infrequent/absent somatic mutations. Other less common presentations included myelodysplastic syndromes (MDS) or MDS/MPN (one each). Four patients presented with B-lymphoblastic leukemia (B-ALL), and of them, two patients with t(8;9)(p22;p24.1) were proven to be B-lymphoblastic crisis of MPN; and the other two cases with t(9p24;v) both were de novo B-ALL, BCR-ABL1-like (Ph-like). We show that the hematopoietic neoplasms with 9p24/JAK2 rearrangement are extremely rare, and most of them are associated with t(8;9)(p22;p24)/PCM1-JAK2, a recent provisional World Health Organization entity under “myeloid/lymphoid neoplasm with a specific gene rearrangement”. Cases of t(8;9)(p22;p24)/PCM1-JAK2, though heterogeneous, do exhibit some common clinicopathological characteristic features. Cases with t(9p24;v)/JAK2 are extremely rare; while such cases with a MPN presentation may resemble t(8;9)(p22;p24.1)/PCM1-JAK2, B-ALL cases presenting de novo B-ALL might belong to Ph-like B-ALL.

PCM1-JAK2 Fusion in a Patient With Acute Myeloid Leukemia

<i>PCM1</i>-<i>JAK2</i> Fusion in a Patient With Acute Myeloid Leukemia

Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities?

Since the publication of the 2001 and 2008 World Health Organization classifications of tumours of haematopoietic and lymphoid tissues, there has been an increasing move towards classification of haematological neoplasms on the basis of the underlying molecular genetic disorder. In recent decades there have been a significant number of reports of haematological neoplasms with rearrangement of JAK2. Published data on such cases have therefore been analysed to determine if any specific entities could be identified. On the basis of this analysis, it is suggested that lymphoid and myeloid neoplasms associated with t(8;9)(p22;p24); PCM1-JAK2 fusion should be recognized as an entity. Furthermore, lymphoid and myeloid neoplasms associated respectively with t(9;12)(p24;p13); ETV6-JAK2 and with t(9;22)(p24;q11·2); BCR-JAK2 should be documented carefully in order to define their features more clearly and assess whether they can be recognized as entities. Identification of all these conditions is important because of the possibility of response to JAK2 inhibitors.

Implication of MAPK1/MAPK3 signalling pathway in t(8;9)(p22;24)/PCM1‐JAK2 myelodysplastic/myeloproliferative neoplasms

Implication of <scp>MAPK</scp>1/<scp>MAPK</scp>3 signalling pathway in t(8;9)(p22;24)/<i><scp>PCM</scp>1‐<scp>JAK</scp>2</i> myelodysplastic/myeloproliferative neoplasms

Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1

The translocation t(8;9)(p22;p24) is a rare event that results in the fusion of JAK2 to PCM1 and thus leads to the activation of the Janus Kinase 2. In 2008, the WHO introduced a new entity called "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1", which are characterized by the formation of a fusion gene encoding an aberrant tyrosine kinase. These disorders share characteristics with myeloproliferative neoplasms and typically show an eosinophilia. We here now report on 6 new cases with PCM1-JAK2 fusion. These patients show characteristics with respect to epidemiology, clinical presentation, and genetic changes that are very similar to patients with rearrangements of PDGFRA, PDGFRB, or FGFR1. Our data suggests the integration of cases with JAK2-PCM1 fusion in the respective WHO category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.

Efficacy of Ruxolitinib in Chronic Eosinophilic Leukemia Associated with t(8;9)(p22;p24) and PCM1-JAK2 Fusion Gene.

AbstractAbstract 2833The 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 × 109/L) with eosinophilia (eosinophils 3.5 × 109/L ), and thrombocytopenia (107 × 109/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.

PCM1-JAK2 Fusion Product Selectively Activates MAP-Kinase Pathway and Fails to Phosphorylate JAK2 and STAT5: Implications for Therapeutic Strategies.

AbstractAbstract 2858Janus-activated kinase 2 (JAK2) gene mutations and translocations are involved in the pathogenesis of a variety of hematologic malignancies. Among different translocation partners, pericentriolar material 1 (PCM1)-JAK2 fusion products have been described in rare cases of both lymphoid and myeloid neoplasms characterized by morphological (myeloproliferaton, eosinophilia, myelofibrosis) and clinical (striking male predominance, aggressive course) similarities.We recently identified a new case of the rare translocation PCM1-JAK2 in a 29-year-old man presenting with atypical chronic myeloid leukemia (aCML) and peculiar aspects of diserythropoiesis in the bone marrow (BM): abundant paratrabecular clusters of proerythroblasts associated with marked reduction of mature erythroid compartment (Sammarelli et al., S.I.E.S. 12th Meeting, 2012).For the first time we describe here the erythroid differentiation capacity of ex-vivo expanded CD34+ cells from this PCM1-JAK2 fusion case, as well as the signaling pathways activated in peripheral blood neoplastic cells (PBNC) harboring the translocation.Presence of the PCM1-JAK2 fusion transcript in PBNC was confirmed by nested RT-PCR using primers derived from PCM1 exon 25 and JAK2 exon 9 described in Reiter et al. Cancer Res. 2005 (Figure 1).CD34+ cells were isolated from the peripheral blood (PB) of the patient and cultured in serum-free medium supplemented with erythropoietin (EPO), interleukin-3 (IL-3) and stem cell factor (SCF) to induce erythroid differentiation; erythroid cell output [evaluated in terms of fold increase (FI) and glycophorin-A (GlyA) expression at day 14 of culture] was compared to the one obtained from PB CD34+ cells from a polycythemia vera patient (PV), in which JAK2 is constitutively activated by V617F point mutation, and to CD34+ cells from a G-CSF-mobilized donor (M).As shown in Figure 2, FI and GlyA expression were significantly lower in our patient compared to M and PV (FI: 0.63, 6.47 and 7.92 respectively; GlyApos cells: 4.2%, 51.6% and 64.2%, respectively) consistently with the diserythropoietic picture in the BM.We then investigated the activation of the 3 main signaling pathways associated to Receptor tyrosine kinases and most commonly turned on in cancer: Mitogen-activated protein (MAP) kinase pathway, JAK/Signal transducer and activator of transcription (STAT) pathway and phosphatidylinositol 3-kinase (PI3K)/AKT pathway, evaluating, by Western Blot analysis, levels of phosphorylation of Extracellular signal-Regulated Kinase (ERK1/2), JAK2, STAT5 and AKT in PBNC from our PCM1-JAK2 case and in PB mononuclear cells (PBMC) from 5 healthy control subjects (C1-C5).Although these signaling cascades are deeply interconnected, we surprisingly found a selective activation of the sole MAP-kinase pathway in PBNC (Figure 3).These data suggest that, while presence of JAK2V617F mutation leads to ligand-independent activation of STAT5, AKT and ERK1/2 (Laubach et al. Exp. Hematol. 2009), PCM1-JAK2 fusion product fails to activate JAK/STAT and PI3K/AKT axis. Specifically, reduced STAT5 activation might explain impaired erythroid differentiation of CD34+ cells in vitro as well as the marked aspects of diserythropoiesis in the BM.The signaling signature of PMC1-JAK2 neoplastic cells described here has also relevant implications on the treatment strategy for these patients. In particular, given the lack of activation of JAK2 and its down-stream partner STAT5, JAK-inhibitor therapy does not seem the ideal candidate in this specific setting. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

PCM1–JAK2-fusion: a potential treatment target in myelodysplastic–myeloproliferative and other hemato-lymphoid neoplasms

Importance of the field: Activating mutations of the JAK2 gene are of tumorigenic significance in myeloproliferative neoplasms. Translocations involving the JAK2 locus are of oncogenic importance in acute leukemias, myelodysplastic/myeloproliferative diseases and T-cell lymphomas. JAK2 locus gains, which are recurrent in Hodgkin's- and primary mediastinal B-cell lymphoma, are also efficient mechanisms of JAK2 activation. Recently, specific drugs blocking JAK2 have been developed and are currently in clinical trials.Areas covered in this review: We discuss possible mechanisms of deregulation and the significance of pericentriolar material 1 (PCM)1–JAK2 fusion/t(8;9)(p21-23;p23-24) in hematolymphoid neoplasms. Such cases show morphological (myeloproliferaton, eosinophilia, myelofibrosis) and clinical (striking male predominance, aggressive course) similarities. Since increased JAK2 oligomerization and tyrosine kinase domain activation is the probable oncogenic mechanism in this instance, such patients are promising candidates for JAK2 inhibitor therapy.What the reader will gain: The reader will gain important insights considering PCM1–JAK2 fusion in hematologic malignancies.Take home message: JAK2 is a tyrosine kinase with oncogenic potential in hematologic malignancies. It can be activated by point mutations, translocations and amplifications. Beyond malignancies associated with JAK2 point mutations, those associated with translocations might be suitable for tyrosine kinase inhibitors, which merits prospective evaluation.

Evolutional change of karyotype with t(8;9)(p22;p24) and HLA-DR immunophenotype in relapsed acute myeloid leukemia

The rare recurrent translocation of (8;9)(p22;p24) with PCM1-JAK2 fusion was recently characterized in diverse hematological malignancies. Most of them are atypical chronic myeloid leukemia (CML) or other myeloproliferative disorders (MPD), and are predominantly in the male. We report a female patient with acute myeloid leukemia (AML) initially presenting with normal karyotype and negative HLA-DR expression who achieved complete remission after standard chemotherapy. The disease relapsed 7 months later with cytogenetic change of t(8;9)(p22;p24). Flow cytometry analysis showed evolutional change of immunophenotype from negative to positive HLA-DR expression and fluorescence in situ hybridization (FISH) analysis demonstrated a PCM1-JAK2 fusion gene. We speculate that the cytogenetic change of t(8;9)(p22;p24) may induce HLA-DR immunophenotypic switch and a coordination of the two evolutional changes may play a role in leukemic cell progression.

A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma

A t(8;9) translocation with PCM1-JAK2 fusion in a patient with T-cell lymphoma