|
| ||
|
|
||
Chronic Myeloproliferative Disorders (chronic + myeloproliferative_disorders)
Selected AbstractsTranscription factor Fli-1 expression by bone marrow cells in chronic myeloproliferative disorders is independent of an underlying JAK2 (V617F) mutationEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2006Oliver Bock Abstract:,Objectives:,Friend leukemia integration-1 (Fli-1), a member of the Ets gene family of transcription factors, has been demonstrated to be a target of a leukaemia inducing virus in mice, and is known to be part of a fusion gene in Ewings' sarcoma in humans. Wild-type Fli-1 is involved in lineage commitment of megakaryocytes and myeloid progenitors through induction of Janus kinases (JAKs) following ligand binding to cytokine and growth factor receptors. Proliferation of atypical megakaryocytes is a predominant histopathological feature in Philadelphia chromosome negative chronic myeloproliferative disorders (Ph, CMPD) and a potential aberrant expression of Fli-1 has not been investigated so far. Methods:,Fli-1 expression was investigated by real-time RT-PCR and immunohistochemistry in bone marrow cells derived from Ph, CMPD (n = 80) and non-neoplastic haematopoiesis (n = 21) following determination of the JAK2 status. Results:,Fli-1 mRNA expression was significantly higher in Essential thrombocythaemia (ET) with JAK2 (V617F) compared with other Ph, CMPD and control (P < 0.001). By immunohistochemistry, Fli-1 protein could be detected in nuclei of atypical megakaryocytes in Ph, CMPD and, less accentuated, in non-neoplastic megakaryocytes. Fli-1 protein expression by myeloid progenitors was considerably heterogenous in Ph, CMPD independent of an underlying JAK2 (V617F) mutation and without notable differences to non-neoplastic haematopoiesis. Conclusion:,Fli-1 is rather constitutively expressed by bone marrow cells in Ph, CMPD independent of the underlying JAK2 status. The overall stronger labelling for Fli-1 in megakaryocytes in Ph, CMPD most likely reflects the degree of polyploidisation but aberrant activation of nuclear target genes can not be excluded. [source] Increased circulating platelet,leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet countEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2001Morten Krogh Jensen Abstract: Platelet,leukocyte adhesion may occur as a consequence of platelet activation and possibly plays a key role in the deposition of activated platelets and fibrin in the thrombotic plug. The aim of the present study was to assess by whole blood flow cytometry the presence of circulating platelet,leukocyte aggregates (PLA) and the platelet,leukocyte response to platelet agonist stimulation (ADP and TRAP) in 50 patients with chronic myeloproliferative disorders (MPD) and 30 controls. PLA were identified as platelet,granulocyte/monocyte aggregates (PGMA), platelet,monocyte aggregates (PMA) and defined as the percentage of leukocytes coexpressing the platelet-specific marker glycoprotein Ib. Compared to controls the mean percentage of PGMA and PMA was increased in unstimulated whole blood from patients with MPD (7.98 vs. 1.76%; p<0.001 and 12.34 vs. 3.2%; p<0.001, respectively). The percentage of PGMA was correlated to the platelet count (r=0.46; p<0.001), percentage of P-selectin (r=0.69; p<0.001) and thrombospondin (r=0.58; p<0.001) positive platelets and platelet expression of GPIV (r=0.33; p=0.02). The mean percentage of PGMA and PMA was significantly increased in ADP-stimulated whole blood of patients (57.14 vs. 47.92%; p=0.009 and 54.91 vs. 45.89%; p<0.001, respectively). Compared to patients without a history of thrombosis, patients having experienced microvascular disturbances or a thrombotic event had a higher mean percentage of PGMA and PMA in non-stimulated whole blood (10.07 vs. 6.34%; p=0.025 and 14.81 vs. 10.48%; p=0.021, respectively) and a higher percentage of PGMA in ADP stimulated whole blood (64.32 vs. 51.50%; p<0.01). These data document an increased frequency of PLA in non-stimulated whole blood in MPD associated with a previous history of thrombosis or microvascular disturbances. [source] Thrombopoietin activates the growth of megakaryoblasts in patients withchronic myeloproliferative disorders and myelodysplastic syndromeEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2000Shigeo Hashimoto Abstract: The effects of thrombopoietin (TPO) on cell proliferation and differentiation, and the relation between these effects and the expression of c-mpl on leukemia cells were studied in seven acute myelogeneous leukemia cell lines and seven myelogeneous blast cell preparations from patients with chronic myeloproliferative disorders (CMPDs) and myelodysplastic syndrome (MDS). Among the leukemia cells, five preparations of megakaryoblastic leukemia cells from patients and one megakaryoblastic cell line, CMK 11.5, proliferated in response to TPO in vitro. CMK 11.5 and the blastic cells from one patient diagnosed with MDS with myelofibrosis differentiated with increasing expression of CD41a in response to TPO. However, TPO had no effect on the cells lacking megakaryocytic characteristics. Some patients with CMPD and MDS develop acute transformation with blasts demonstrating megakaryocytic features, and some of these cells show growth in response to TPO. Therefore, in vivo administration of TPO should be considered carefully for patients with CMPD or MDS, since TPO may induce leukemic cell proliferation. [source] Peripheral T-cell lymphoma presenting as myelofibrosis with the expression of basic fibroblast growth factorGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2009Masayuki Kikukawa Myelofibrosis is often observed in chronic myeloproliferative disorders (CMPD), but non-Hodgkin's lymphoma with diffuse myelofibrosis is rare. We describe an elderly case with peripheral T-cell lymphoma-unspecified (PTCL) presenting as diffuse myelofibrosis. Bone marrow biopsy revealed infiltration of atypical lymphocytes and diffuse myelofibrosis without any increase in megakaryocytes. To discuss the pathogenesis of fibrosis, we examined cytokines relative to fibrosis using immunostaining. The expression of basic fibroblast growth factor (bFGF) was diffusely detected in the area of extracellular matrix of bone marrow. In addition, in situ hybridization revealed that infiltrating lymphoma cells expressed bFGF mRNA. Basic FGF, originally identified based on its mitogenicity for fibroblasts, has multiple potential, influencing neoangiogenesis, bone marrow fibrosis and the proliferation of tumor cells. Basic FGF might play an important role in the pathogenesis of myelofibrosis in the present case. [source] New perspectives in managing myeloproliferative disorders: focus on the patient,HEMATOLOGICAL ONCOLOGY, Issue S1 2009Gunnar Birgegård Abstract Risk stratification is the basis for treatment decisions in the chronic myeloproliferative disorders, and in addition to the three established risk factors of previous thrombosis, age and platelets >1500,×,109, cardiovascular risk factors should be addressed. In addition, premorbidity with regard to possible side effects of platelet-reducing drugs as well as the impact on quality of life of such side effects should be considered. The near-to-normal life expectancy and long term nature of treatment also makes it necessary to consider the potential leukaemogenic effects of some cytostatic drugs. Copyright © 2009 John Wiley & Sons, Ltd. [source] Familial chronic myeloproliferative disorders: the state of the art,HEMATOLOGICAL ONCOLOGY, Issue 3 2008Elisa Rumi Abstract Familial chronic myeloproliferative disorders are defined when in the same pedigree at least two relatives have a chronic myeloproliferative disorder (CMD) as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). This condition should be distinguished from inherited disorders with Mendelian transmission and single haematopoietic lineage proliferation, named hereditary erythrocytosis and thrombocytosis. The recently discovered mutations in patients with CMD (V617F and exon 12 of JAK2 gene, MPL gene), and those identified in hereditary erythrocytosis and in hereditary thrombocytosis have improved our ability to discriminate these conditions. In familial CMD, the JAK2 mutations are acquired and occur as secondary genetic events. As both mutations of the JAK2 gene have been reported in the same pedigree, a genetic predisposition to the acquisition of the JAK2 mutations is supposed to be inherited. The prevalence of familial cases within CMD is at least 7.6%. The inheritance pattern of familial CMD is consistent with an autosomal dominant trait with decreased penetrance. The clinical presentation at diagnosis of patients with familial CMD does not differ from that of patients with sporadic CMD. In addition, patients with familial CMD develop the same type of complications (thrombosis and haemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis and leukaemia) observed in patients with sporadic CMD. The 10-year survival is 83% for patients with familial PV, 100% for those with familial ET, and 30% for those with familial PMF. The aim of this review is to focus the state of the art of familial CMD and to offer an overview of inherited conditions causing erythrocytosis and thrombocytosis. Copyright © 2008 John Wiley & Sons, Ltd. [source] Idiopathic myelofibrosis: pathogenesis to treatmentHEMATOLOGICAL ONCOLOGY, Issue 2 2006John T Reilly Abstract Idiopathic myelofibrosis (IMF) is the least common of the chronic myeloproliferative disorders and carries the worst prognosis with a median survival of 4 years. It is a clonal haematopoietic stem-cell disorder and, although the pathogenesis remains unclear, approximately 50% of cases are known to possess an activating JAK2 V617F mutation. In contrast, the characteristic stromal proliferation is a reactive, or secondary, event that results from the aberrant release of a variety of growth factors from megakaryocytes and monocytes. Treatment for most cases is supportive, although androgens, recombinant erythropoietin, steroids and thalidomide are effective modalities for the amelioration of anaemia. Myelosuppression, splenectomy and irradiation are valuable therapeutic modalities for specific clinical situations. Prognostic scores are available to aid the identification of cases for whom bone marrow transplantation should be considered. Recently, the use of reduced intensity conditioning has resulted in prolonged survival and lower transplant-related mortality. This review summarises the recent advances in the disease's pathogenesis and discusses the role of the various therapeutic options. Copyright © 2006 John Wiley & Sons, Ltd. [source] Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disordersJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2007V. DE STEFANO Summary., Background:, Thrombosis of splanchnic or cerebral veins is a typical manifestation of polycythemia vera (PV) or essential thrombocythemia (ET). The recently identified Janus kinase 2 (JAK2) V617F somatic mutation is closely related to chronic myeloproliferative disorders (CMD). Objective:, To assess the incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis with or without overt CMD. Patients and methods:, We searched for the mutation in 139 adult patients (> 18 years old) with thrombosis of hepatic veins (HVT, n = 15), or extrahepatic portal vein (PVT) and/or mesenteric vein (MVT) (n = 79), or cerebral veins (CVT, n = 45). Only 19 patients fulfilled criteria for diagnosis of PV (n = 8) or ET (n = 11) at the time of thrombosis: four had HVT, 11 PVT and/or MVT, and four CVT. Results:, The JAK2 V617F mutation was found in 94.7% [95% CI 75.3,99.0] of the patients with overt CMD at the time of thrombosis, in 21.5% (95% CI 13.8,31.7) of the patients with abdominal venous thrombosis and without overt CMD, and in 4.8% (95% CI 1.3,16.1) of the patients with CVT and without overt CMD. Among the patients without overt CMD or thrombophilia and with unprovoked thrombosis, 29.4% (95% CI 16.8,46.1) with splanchnic venous thrombosis and 42.8% (95% CI 24.4,63.4) with PVT had the JAK2 V617F mutation. Conclusions:, A substantial proportion of patients with splanchnic venous thrombosis and a small, but significant, number of patients with CVT can be recognized as carriers of the JAK2 V617F mutation in the absence of overt signs of CMD. The clinical significance of such findings deserves further investigation. [source] Factor V Leiden mutation carriership and venous thromboembolism in polycythemia vera and essential thrombocythemiaAMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2002Marco Ruggeri Abstract Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are chronic myeloproliferative disorders complicated by a high incidence of thrombotic complications. Extensive coagulation studies failed to demonstrate a consistent pattern of abnormalities associated with thrombosis. Recently, a poor anticoagulant response to activated protein C (APC), due to a mutation of factor V (FV Leiden), has been identified as the most frequent hereditary disorder associated with venous thrombophilia. We investigated in 304 patients with PV and ET whether the presence of FV Leiden could be a risk factor for thrombosis. FV Leiden was found in 14/304 patients (4.6%) and was associated with venous thromboembolism (VTE) occurred before and at diagnosis (5/27,16%, with a significant difference of prevalence in comparison of that observed in asymptomatic patients, 9/263, 3%, p = 0.003). Carriership of FV Leiden was associated with VTE relapse, with a prevalence of 3.6% in asymptomatic patients, 6.9% in patients with a single episode of VTE and 18.1% in patients with recurrent VTE. The prevalence of FV Leiden in patients with and without arterial thrombosis was similar (5/79, 6% and 9/211, 4%, respectively, p = 0.337). This study indicates that the prevalence of the FV Leiden mutation in patients with PV and ET is comparable with that observed in the general population. FV Leiden mutation is a risk factor for VTE before and at time of diagnosis and for VTE recurrences. Screening for FV Leiden may be considered to identify PV and ET patients at higher risk of recurrences. Am. J. Hematol. 71:1,6, 2002. © 2002 Wiley-Liss, Inc. [source] The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disordersBRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2007Thomas Stauffer Larsen Summary The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Phneg. -CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards to phenotype. The mutation is found in the majority of patients with PV and about half of the patients with ET and IMF. These diseases are clonal stem cell disorders arising in an early stem cell progenitor. The level in the stem cell hierarchy on which the initiating genetic events and the JAK2 V617F mutation occurs is not known. The mutation has so far been detected in all cells of the myeloid lineage, whereas the potential clonal involvement of the lymphoid lineage is controversial. In this study, we detected the JAK2 V617F mutation by real-time quantitative PCR (qPCR) in both B-lymphocytes and T-lymphocytes in a subgroup of patients with Phneg. -CMPDs. These results demonstrate the origin of the JAK2 V617F positive disorders in an early stem cell with both lymphoid and myeloid differentiation potential. [source] Prospective application of a multiplex reverse transcription-polymerase chain reaction assay for the detection of balanced translocations in leukaemia: a single-laboratory study of 390 paediatric and adult patientsBRITISH JOURNAL OF HAEMATOLOGY, Issue 1 2004Lene Hyldahl Olesen Summary The upfront application of molecular methods for identifying the fusion transcripts arising from balanced translocations in haematopoietic malignancies has several advantages: sensitivity is independent of its frequency, i.e. rare ones are not missed, cytogenetically cryptic aberrations are identified and it provides a platform for minimal residual disease (MRD) detection. Employing a multiplex reverse transcription polymerase chain reaction (RT-PCR) assay identifying 27 fusion transcripts we prospectively analysed blood and/or bone marrow samples from 390 patients referred for diagnosis and treatment for acute leukaemia and chronic myeloproliferative disorders (CMPD) from a geographically well-defined region in Denmark. A total of 233 patients were diagnosed with acute myeloid leukaemia (AML), 95 with acute lymphoblastic leukaemia (ALL) origin and 62 patients were recorded as CMPD. Twenty-three percent AML, 32% ALL and 55% CMPD patients exhibited chromosomal aberrations detected by the multiplex RT-PCR. Cytogenetically cryptic translocations were seen in 15% of the cases. Conversely, the cytogenetic analysis identified chromosomal aberrations other than translocations in 45% of AML cases and 63% of ALL cases. We conclude that, while the fraction of translocation positive leukaemia patients in an unselected cohort is lower than hitherto believed, a molecular approach to their diagnosis is worthwhile, partly for identifying cryptic and rare translocations, partly for monitoring MRD. [source] | ||||||||||||||||||||||