Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polycythemia vera (PV) is a clonal disorder of unknown etiology involving a multipotent hematopoietic progenitor cell that is characterized by the accumulation of phenotypically normal red blood cells, white blood cells, and platelets in the absence of a definable cause; extramedullary hematopoiesis, marrow fibrosis, and, in a few patients, transformation to acute leukemia can also occur. First described in 1892, the cause of the disease remains unknown and no potentially curative therapy other than bone marrow transplantation is currently available. It is commonly held that PV is a rare disorder, when in fact with a minimum incidence of 2.6 per 100,000 it is more common than chronic myelogenous leukemia (CML) and is particularly prevalent in persons of Ashkenazi Jewish ancestry. However, the incidence of PV is not as high as that of erythrocytosis from other causes collectively, which poses a problem in differential diagnosis when PV presents as isolated erythrocytosis. Characteristic features of PV are erythropoietin (Epo)-independent in vitro erythroid colony formation, as well as hypersensitivity to many other hematopoietic growth factors. Recently, a remarkable association between PV and a somatic point mutation of the JAK2 tyrosine kinase (JAK2 V617F) was described. Functional assays have revealed that JAK2 V617F is capable of inducing constitutive STAT5-mediated signaling in vitro, as well as erythrocytosis in vivo in mice. These data suggest that the JAK2 V617F mutation participates in the pathogenesis of PV. In current clinical practice, two different clinical approaches have been used to diagnose PV. One approach requires establishing the presence of absolute erythrocytosis by directly determining the red cell mass (RCM). A second approach utilizes a RCM-independent diagnostic algorithm based on the serum Epo level and bone marrow histology. Screening for JAK2 V617F can now be added to both diagnostic algorithms. However, it is very clear that some patients with classical PV lack the JAK2 V617F mutation, while some patients with other chronic myeloproliferative disorders such as idiopathic myelofibrosis (IMF) and essential thrombocytosis (ET) also express the JAK2 V617F mutation. Therefore, by necessity, any discussion of PV must take into consideration these companion myeloproliferative disorders, and since erythrocytosis is the single clinical feature that sets PV apart from IMF and ET, it is clear that the presence of the JAK2 V617F mutation cannot by itself establish a diagnosis of PV. Phlebotomy remains the mainstay of therapy for PV. In addition, both aspirin and cytoreductive therapy have been employed to control thrombocytosis and in the case of the latter, leukocytosis and extramedullary hematopoiesis as well. Despite recent progress in the field, several important issues remain controversial. In this review, we will present the areas of agreement, but also point out where the authors' personal viewpoints differ.
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PMID:Polycythemia vera: scientific advances and current practice. 1621 34

To study the gene expression profile in K562 cells treated by IFN-alpha, so as to provide some information about the potential mechanism of IFN-alpha curing CML, the changes of gene expression were examined with the DNA array in K562 cells before and after treatment with IFN-alpha. The results showed that no gene expression difference more than 2.5 times in K562 cells was found on the first day after treatment with IFN-alpha (200 U/ml), then the genes significant expression difference increased step by step, and reached the peak on the forth day. In all examined genes, 97 genes significant expression difference were detected, 86.60% (84/97) gene of interest out of those gene were up-regulated, 13.40% (13/97) were down-regulated. In these 97 genes with significant expression difference, cell regulator protein genes accounted to 23.71% (23/97), surface receptor genes 14.43% (14/97), oncogenes and tumor suppressors 11.34% (11/97), extracellular communication proteins 9.28% (9/97), cell adhesion molecular genes 8.25% (8/97) and the other genes accounted to 32.99% (32/97). JAK1 was up-regulated to 3.78 times, JAK2 to 15.43, STAT1 and STAT2 were up-regulated to 11.98 and 8.11 times respectively, and these genes are components of JAK-STAT pathway. The number of different genes began to decrease on the fifth day. There were still 9 genes that had expression difference more than 3 times on the twenty-first day. It is concluded that when concentration of IFN-alpha was 200 U/ml, the forth day should be considered as the best time to examine change of gene expression in K562 cells treated by IFN-alpha. IFN-alpha realizes its biological functions through the JAK-STAT pathways and it may be one of the mechanisms for curing CML with IFN-alpha.
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PMID:[Gene expression profile in K562 cells treated by interferon alpha]. 1627 35

Myeloproliferative disorders (MPDs) are heterogeneous diseases that occur at the level of a multipotent hematopoietic stem cell. They are characterized by increased blood cell production related to cytokine hypersensitivity and virtually normal cell maturation. The molecular pathogenesis of the MPDs has been poorly understood, except for chronic myeloid leukemia (CML), where the Bcr-Abl fusion protein exhibits constitutive kinase activity. Since some rare MPDs are also related to a dysregulated kinase activity, a similar mechanism was thought to be likely responsible for the more frequent MPDs. We investigated the mechanisms of endogenous erythroid colony formation (EEC) by polycythemia vera (PV) erythroid progenitor cells and found that EEC formation was abolished by a pharmacological inhibitor of JAK2 as well as an siRNA against JAK2. JAK2 sequencing revealed a unique mutation in the JH2 domain leading to a V617F substitution in more than 80% of the PV samples. This mutation in the pseudokinase autoinhibitory domain results in constitutive kinase activity and induces cytokine hypersensitivity or independence of factor-dependent cell lines. Retroviral transduction of the mutant JAK2 into murine HSC leads to the development of an MPD with polycythemia. The same mutation was found in about 50% of patients with idiopathic myelofibrosis (IMF) and 30% of patients with essential thrombocythemia (ET). Using different approaches, four other teams have obtained similar results. The identification of the JAK2 mutation represents a major advance in our understanding of the molecular pathogenesis of MPDs that will likely permit a new classification of these diseases and the development of novel therapeutic approaches.
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PMID:A unique activating mutation in JAK2 (V617F) is at the origin of polycythemia vera and allows a new classification of myeloproliferative diseases. 1630 80

Chronic myeloproliferative diseases (CMPDs) are characterized by the abnormal proliferation and survival of one or more myeloid cell types. The archetype of this class of hematological diseases is chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia (Ph) chromosome, the result of t(9;22)(q34;q11), and the associated BCR-ABL1 oncogene. Some of the Ph-negative myeloproliferative diseases are characterized by other chromosomal translocations involving a variety of tyrosine kinase genes, including ABL1, ABL2, PDGFRA, PDGFRB, FGFR1, and JAK2. The majority of Ph-negative CMPDs, however, such as chronic eosinophilic leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are not characterized by the presence of recurrent chromosomal abnormalities. Recent studies have identified the FIP1L1-PDGFRA fusion gene, generated due to a small cryptic deletion on chromosome 4q12, and the activating V617F mutation in JAK2 in a significant fraction of Ph-negative CMPDs. These results show that abnormalities in tyrosine kinase genes are central to the molecular pathogenesis of CMPDs. Genome-wide screenings to identify novel tyrosine kinase abnormalities in CMPDs may contribute to further improvement of the diagnosis and the treatment of these diseases.
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PMID:Chronic myeloproliferative disorders: a tyrosine kinase tale. 1634 Oct 34

Following the introduction of the WHO classification of chronic myeloproliferative disorders (MPDs), after approximately 5 years, a critical reappraisal appears to be warranted. Retrospective clinico-pathological evaluations conducted in the meantime, as well as the detection of new biomarkers, may aid in testing the validity of these new criteria. Based on a large series of patients with chronic myeloid leukemia (CML), an analysis of bone marrow (BM) features and risk classifications revealed that the fiber content exerted a most important and independent impact on prognosis. This finding was also supported in a prospective randomized study and therefore myelofibrosis should be included in any staging system in CML related to survival. Moreover, it is important to emphasize the dynamics of the disease process in MPDs, especially in polycythemia vera (PV) and chronic idiopathic myelofibrosis (CIMF). Latent-stage PV is difficult to recognize when adhering to the proposed limits for hemoglobin (or red cell mass) without regarding the erythropoietin (EPO) level, endogenous erythroid colonies (EECs) or BM histopathology. Initial PV may firstly present with complications and, when accompanied by a high platelet count, mimics essential thrombocythemia (ET). Consequently, BM morphology and EPO level should be entered as major diagnostic criteria for PV. To document more accurately the progress of disease, a simplified scoring system concerning myelofibrosis has to be included in the histological description of CIMF. The diagnostic guidelines of BM features in ET should be improved because, usually, there is neither a significant proliferation nor left-shifting of the granulo- and erythropoiesis detectable and no relevant increase in reticulin. A comparison of clinical data and BM morphology reveals that biomarkers (EPO, EECs, PRV-1, JAK2) show an overlapping pattern of positivity between the different subtypes of MPDs.
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PMID:A critical reappraisal of the WHO classification of the chronic myeloproliferative disorders. 1639 60

In this study, we examined highly enriched CD34+ cells from patients with BCR-ABL-positve CML in chronic phase or blast crisis for the JAK2 V617F activation mutation by sequencing. The cells examined did not bear the mutation irrespective of the disease stage. This finding suggests that the previously described increase of expression and kinase activity of JAK2 in CML cells does not result from the JAK2 V617F activation mutation and that transformation into blast crisis is not associated with the occurrence of this mutation.
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PMID:Absence of the JAK2 mutation V617F in CD34+ hematopoietic stem and progenitor cells from patients with BCR-ABL-positive CML in chronic phase and blast crisis. 1644 19

Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B -/- bone marrow presents no abnormalities at the granulocyte-monocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B -/- cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.
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PMID:Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling. 1647 24

To study the prevalence of the Val617Phe JAK2 mutation in familial cases of myeloproliferative disorder (MPD) and its possible implication as a predisposing genetic factor, we analyzed 72 families including 174 patients (81 polycythemia vera [PV], 68 essential thrombocythemia [ET], 11 myelofibrosis with myeloid metaplasia [MMM], 12 chronic myeloid leukemia), 1 systemic mastocytosis, and 1 chronic myelomonocytic leukemia (CMML). The JAK2 mutation was found in three quarters of patients with PV and MMM and in half of patients with ET. Among 46 families with at least 2 cases of PV, ET, or MMM, the JAK2 mutation was absent in 6 families, heterogeneously distributed in 18, and present in all MPD patients in 22. Among these 22 families, the absence of the JAK2 mutation both in purified T and B cells in 13 unrelated patients and the observation of variable ratios of the JAK2 mutant allele in patient leucocytes indicated that the Val617Phe JAK2 mutation was acquired in familial MPDs. The JAK2 mutation was present in natural killer cells in two thirds of tested patients (27 of 40), suggesting its occurrence in a multipotent hematopoietic progenitor cell. The analysis of the hematologic profile showed that the homozygous JAK2 mutation confers a proliferative advantage and is associated with the progression of the hematologic disease.
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PMID:Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. 1653 3

We developed and validated a real-time polymerase chain reaction assay using fluorescent hybridization probes and melting curve analysis to identify the JAK2 V617F mutation, which is implicated in a substantial proportion of chronic myeloproliferative disorders (CMPDs). DNA from 161 samples was isolated from peripheral blood granulocytes and formalin-fixed bone marrow clot sections in patients with CMPDs and without myeloproliferative disorders previously genotyped for the JAK2 V617F (G-->T) mutation, which included 114 wild types (GG) and 47 mutants (GT and TT). Melting curve analysis of these samples yielded 114 wild types, 42 heterozygotes, and 5 homozygotes showing 100% concordance. Analytic sensitivity of the assay for mutant DNA was 5% for the LightTyper (Roche Applied Sciences, Indianapolis, IN) and 10% for the LightCycler (Roche Applied Sciences). Consistent with earlier reports, 78% of the non-chronic myelogenous leukemia CMPD patients and 8% of non-CMPD patients displayed this mutation. This study demonstrates that clinical genotyping of the JAK2 V617F mutation can be performed by melting analysis using both freshly isolated and formalin-fixed tissues.
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PMID:Identification of the JAK2 V617F mutation in chronic myeloproliferative disorders using FRET probes and melting curve analysis. 1670 63

Hematological malignancies are phenotypically organized into lymphoid and myeloid disorders, although such a distinction might not be precise from the standpoint of lineage clonality. In turn, myeloid malignancies are broadly categorized into either acute myeloid leukemia (AML) or chronic myeloid disorder (CMD), depending on the presence or absence, respectively, of AML-defining cytomorphologic and cytogenetic features. The CMD are traditionally classified by their morphologic appearances into discrete clinicopathologic entities based primarily on subjective technologies. It has now become evident that most CMD represent clonal stem cell processes where the primary oncogenic event has been characterized in certain instances; Bcr/Abl in chronic myeloid leukemia, FIP1L1-PDGFRA or c-kit(D816V) in systemic mastocytosis, rearrangements of PDGFRB in chronic eosinophilic leukemia, and rearrangements of FGFR1 in stem cell leukemia/lymphoma syndrome. In addition, Bcr/Abl-negative classic myeloproliferative disorders are characterized by recurrent JAK2(V617F) mutations, whereas other mutations affecting the RAS signaling pathway molecules have been associated with juvenile myelomonocytic leukemia. Such progress is paving the way for a transition from a histologic to a semi-molecular classification system that preserves conventional terminology, while incorporating new information on molecular pathogenesis.
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PMID:Classification of chronic myeloid disorders: from Dameshek towards a semi-molecular system. 1678 78


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