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Query: UMLS:C0023473 (chronic myeloid leukemia)
18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia constitute the "classic" bcr/abl-negative myeloproliferative disorders (MPDs). Each of these MPDs represents a stem cell-derived clonal myeloproliferation with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. Unlike with cases of chronic myeloid leukemia, in which the bcr/abl mutation is invariably detected, current diagnosis of essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia is based on a consensus-driven set of clinical and laboratory criteria that have undergone substantial modification in recent times. The recent discovery of a recurrent activating Janus tyrosine kinase (JAK2) mutation (JAK2VG17F) in all 3 classic MPDs offers another opportunity for refining current diagnoses and disease classifications. In this article, we outline contemporary diagnostic algorithms for each of these disorders and provide an evidence-based approach to management.
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PMID:bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment. 1617 3

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

Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands re-evaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand.
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PMID:JAK2 V617F in myeloid disorders: what do we know now, and where are we headed? 1632 48

The recent discovery of a single point mutation in the JH2 pseudokinase domain of Janus kinase 2 (JAK2) in a considerable fraction of patients has shed light on the molecular pathomechanism in Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph- CMPDs). We established a robust and reliable method for detection of the JAK2 mutation in bone marrow cells derived from archival bone marrow trephines based on polymerase chain reaction and subsequent restriction site analysis. In a series of proven Ph- CMPDs classified according to World Health Organization criteria (n = 79), we detected the JAK2 mutation in 90% of polycythemia vera, 22% of cellular prefibrotic chronic idiopathic myelofibrosis, 60% of advanced chronic idiopathic myelofibrosis, and 27% of essential thrombocythemia. JAK2 mutation was not detected in Ph+ chronic myeloid leukemia (n = 5), acute myeloid leukemia (n = 10), acute lymphoblastic leukemia (n = 10), secondary erythrocytosis (n = 10), or normal bone marrow (n = 10). Restriction site analysis was also suitable for unfixed cell populations derived from peripheral blood and bone marrow aspirates. Besides providing support in the differential diagnosis of reactive versus neoplastic myeloproliferations, this newly developed assay reveals considerable overlaps between histologically different disease entities, indicating that additional genetic alterations might be responsible for the established differences of CMPD subentities.
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PMID:Detection of the single hotspot mutation in the JH2 pseudokinase domain of Janus kinase 2 in bone marrow trephine biopsies derived from chronic myeloproliferative disorders. 1664 2

The discovery of the activating V617F mutation in the JAK2 tyrosine kinase in a high proportion of patients with Ph- chronic myeloproliferative diseases (CMPD) represents a diagnostic breakthrough for these disorders. Trephine bone marrow biopsy is an essential part of the diagnostic workup of CMPD and represents a valuable archival source of DNA. Therefore, we studied 152 paraffin-embedded trephines with CMPD and related disorders for the presence of the V617F mutation, using both allele-specific polymerase chain reaction (PCR) and nested PCR with subsequent digestion with BsaXI. Only 6 of 152 (4%) samples were not evaluable because of poor DNA quality. The V617F mutation was detected in 27 of 28 (96%) cases of polycythemia vera, 17 of 23 (74%) cases of essential thrombocythemia, 28 of 45 (62%) cases of chronic idiopathic myelofibrosis, six of eight (75%) cases of CMPD unclassified, and two of four (50%) cases of myelodysplastic/myeloproliferative syndrome. Ph+ chronic myelogenous leukemia (four cases), reactive (secondary) erythrocytosis (14 cases), and thrombocytosis (one case) as well as normal controls (19 cases) all lacked the V617F mutation. Based on results of BsaXI digestion and sequencing, 24 of 54 (44%) evaluable V617F+ cases were considered homozygously mutated. Thus, detection of the V617F JAK2 mutation is feasible in paraffin-embedded trephine biopsies and represents a major advance in the diagnostic evaluation of CMPD.
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PMID:Detection of the activating JAK2 V617F mutation in paraffin-embedded trephine bone marrow biopsies of patients with chronic myeloproliferative diseases. 1682 1

Detection of genetic markers improves diagnostic refinement of chronic myeloproliferative disorders (CMDs) and is helpful in discriminating reactive conditions mimicking CMDs such as reactive erythrocytosis and thrombocytosis. We set-up a multiplex real-time polymerase chain reaction assay followed by capillary electrophoresis, designed to simultaneously screen the two main genetic lesions associated with CMDs, i.e. the BCR-ABL fusion characteristic of chronic myeloid leukemia and the JAK2 V617F mutation that characterises polycythaemia vera and a proportion of cases of essential thrombocythemia and idiopathic myelofibrosis. The test was used in the diagnostic work-up of 50 patients with elevation of >or=2 myeloid cell types in their blood count at presentation and in 42 patients with isolated, non-reactive thrombocytosis. This approach refined diagnosis in 44 of 50 cases in the first series and in 22 of 42 cases with isolated thrombocytosis. We conclude that this non-isotopic and rapid assay amenable to automation may be adopted in routine genetic diagnosis of CMDs as well as for initial screening of thrombocytosis of unknown nature.
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PMID:Diagnostic refinement of chronic myeloproliferative disorders and thrombocytoses of unknown origin by multiple RT-PCR and capillary electrophoresis of BCR-ABL rearrangements and JAK2 (V617F) mutation. 1728 76

The bone marrow criteria defined by the World Health Organization (WHO) are based on characteristic increase and clustering of morphologically abnormal enlarged megakaryocytes as a pathognomonic clue to describe three distinct phenotypic entities of myeloproliferative disorders (MPDs): (1) essential thrombocythemia (ET), (2) early and overt polycythemia vera (PV) and (3) prefibrotic, early fibrotic, and fibrotic chronic idiopathic myelofibrosis (CIMF-0, 1, 2 and 3). Based on established WHO bone marrow features, and the use of new molecular and laboratory markers including JAK2(V617F) mutation, endogenous erythroid colony (EEC) formation and serum erythropoietin (EPO), we present updated European clinical, molecular and pathological (ECMP) criteria for the differential diagnosis of true ET, PV and CIMF. As compared to the WHO bone marrow features, each of the laboratory and molecular markers are not sensitive enough for the diagnosis and classification of the three prefibrotic MPDs. The proposed WHO/ECMP criteria reduce the platelet count to the upper limit of normal (>400x10(9)l(-1)) as inclusion criterion for the diagnosis of thrombocythemia in true ET, early stages of PV and prefibrotic CIMF. The combined use of WHO and ECMP criteria differentiate PV from congenital and acquired erythrocytosis, true ET from reactive thrombocytosis and separates true ET from CIMF-0/1 mimicking ET. Only half of the patients with true ET and CIMF carry the JAK2(V617F) mutation (sensitivity 50%). Early PV mimicking ET is featured by the presence of JAK2(V617F) mutation, EEC, low serum EPO levels, normal hematocrit, and increased bone marrow cellularity due to increased erythropoiesis ("forme fruste" PV) when WHO/ECMP criteria are applied. The combination of JAK2(V617F) PCR test and increased hematocrit is diagnostic for PV (sensitivity 95%, specificity 100%). The degree of JAK2(V617F) positivity of granulocytes is related to disease stage: heterozygous in true ET and early PV and mixed hetero/homozygous to homozygous in overt and advanced PV and CIMF. Bone marrow histology assessment should remain the gold standard criterion for the diagnosis and staging of the MPDs true ET, PV and CIMF and its differentiation from primary or secondary erythrocytosis, reactive thrombocytosis and thrombocythemias associated with atypical MPD, myelodysplastic syndromes, and chronic myeloid leukemia,. The proposed WHO/ECMP criteria allow a cross talk between clinicians, pathologists and scientists to much better characterize the nature and natural history of each of the WHO/CMP defined early and overt MPDs.
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PMID:WHO bone marrow features and European clinical, molecular, and pathological (ECMP) criteria for the diagnosis of myeloproliferative disorders. 1736 53

Histomorphological evaluation of bone marrow trephines and smears represents the major approach to diagnose the chronic myeloproliferative diseases (CMPD) and the myelodysplastic syndromes (MDS). However, rising insights into molecular pathogenesis of human diseases strengthen the attempt of pathologists to define and to detect underlying defects beyond the microscope. Since discovery of the Philadelphia chromosome in chronic myeloid leukemia as the first specific molecular abnormality ever detected in a human neoplasia the gain of knowledge of molecular pathomechanisms in Philadelphia chromosome negative (Ph-) CMPD was rather sparse. A decisive breakthrough in Ph CMPD was the finding of JAK2 (V617F) derived from a somatic point mutation in the majority of patients with polycythemia vera (P.vera) and half of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). It therefore can not be overestimated that detection of JAK2 (V617F) in a suspective myeloproliferation now enables a clearcut discrimination of a true Ph CMPD from a reactive state, e.g. P.vera from reactive erythrocytosis. Interestingly, a basic principle of molecular defects demonstrable in CMPD and related disorders seems to be the involvement of genes with kinase activities. Some of those genes will be discussed in more detail. In primary MDS, karyotyping via classical cytogenetics is the predominant molecular approach to estimate prognosis, e.g. -Y, del(5q) and del(20q) represent favourable anomalies. Indeed, in 5q- syndromes karyotyping enables definite subtyping and allows clinicians and patients to expect a good prognosis. Until now, dozens of molecular abnormalities such as mutations in AML1, FLT3 and Ras as well as epigenetic alterations of genes have been identified to various degrees in MDS subtypes. Some of them seem to be involved in disease initiation ("master event") and others might indicate disease progression. However, even though useful for further dissection of molecular pathomechanisms the majority of aberrations currently does not serve as potent markers in the daily routine. Nevertheless, in CMPD and MDS the importance of molecular analyses for diagnosis, estimation of prognosis, and disease monitoring will further increase in a foreseeable period of time.
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PMID:[Molecular diagnosis of chronic myeloproliferative diseases and myelodysplastic syndromes]. 1831 8

This review focuses on topical issues in the biology and treatment of the myeloproliferative neoplasms (MPNs). Studies in transgenic mice suggest that BCR-ABL1 reduces the fraction of self-renewing 'leukemic' stem cells in the bone marrow but that some of these cells survive treatment with imatinib. This also seems to operate in humans. Data from models also strongly support the notion that JAK2(V617F) can initiate and sustain MPNs in mice; relevance to disease in humans is less clear. These data also support the hypothesis that level of JAK2(V617F) expression influences the MPN phenotype: higher levels favor erythrocytosis whereas lower levels favor thrombocytosis. Although TET2-mutations were thought to precede JAK2(V617F) in some persons with MPNs, it now appears that TET2 mutations may occur after JAK2(V617F). Further understanding of signal-transduction pathways activated in chronic myeloid leukemia suggests various possible targets for new therapies including the WNT/beta catenin, notch and hedgehog pathways. Finally, the clinical role of the new JAK2- and BCR-ABL1-inhibitors is considered. Much further progress is likely in several of these areas soon.
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PMID:The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre-clinical and clinical issues. 2124 85

The present report describes two chronic myelogenous leukemia (CML) patients with the JAK2-V617F mutation who were in complete hematologic and cytogenetic remission and subsequently developed clinical features of essential thrombocythemia under treatment with tyrosine kinase inhibitors. In light of the findings from previous reports, screening for the JAK2-V617F mutation should be considered for any Ph(+) CML patients with thrombocytosis, leukocytosis, or erythrocytosis at diagnosis and for patients who subsequently develop thrombocytosis, leukocytosis, or erythrocytosis during follow-up, even for CML patients in complete cytogenetic response and major molecular response.
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PMID:Two CML patients who subsequently developed features of essential thrombocythemia with JAK2-V617F mutation while in complete cytogenetic remission after treatment with imatinib mesylate. 2361 67

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