Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiation. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) or overexpression of these enzymes plays an etiologic role in several clonal hematopoietic malignancies. Other than the causative effect of PTK product of the bcr/abl fusion gene on chronic myelogenous leukemia (CML), more evidence suggests that mutated tyrosine kinases are pivotal in the pathogenesis of most of other chronic myeloproliferative disorders, such as chronic myelomonocytic leukemia (CMML) and hypereosinophilic syndrome (HES). And the exciting results in several dependent groups in 2005 showed that a single nucleotide JAK2 somatic mutation (JAK2V617F mutation) was found to be involved in the pathogenesis of polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF). In the leukogenesis of acute myeloid leukemias (AML), the losing of the control of the proliferation of hematopoietic progenitor cells was principally the results of the aberrant PTK activity, such as FLT3 and C-kit overexpression. It works together with the loss of function mutation genes in promoting progenitor cell differentiation to confer AML's phenotypes. These upregulated PTK molecules represent attractive disease-specific targets, to which a new class of therapeutic agents are being developed. This review focuses on abnormal tyrosine kinases that have been involved in the pathogenesis of hematopoietic malignancies.
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PMID:[Abnormal activation of tyrosine kinases and its role in the pathogenesis of hematological malignancies - review]. 1760 88

Extramedullary hematopoiesis (EMH) in the spleen is a characteristic feature of the chronic myeloproliferative disorders (CMPDs) and various other neoplastic or reactive myeloid conditions. However, the origin of these hematopoietic precursor cells and the molecular mechanisms underlying their development in the spleen is uncertain. The V617F mutation in the Janus Kinase 2 gene (JAK2(V617F)) was recently shown to be frequently and preferentially present in the peripheral blood and bone marrow cells of CMPD patients, and the resulting dysregulation of its downstream targets is important to CMPD pathogenesis. To determine the occurrence and potential role of JAK2(V617F) in splenic EMH cells, we studied splenectomy specimens from 47 patients with significant EMH. JAK2(V617F) was detected by real-time PCR melting curve analysis in 22 specimens, including 11/17 chronic idiopathic myelofibrosis, 7/7 polycythemia vera, 1/1 essential thrombocythemia, 1/3 CMPD unclassifiable, 1/5 chronic myelomonocytic leukemia, 0/5 chronic myelogenous leukemia, 1/3 myelodysplastic syndrome and 0/6 acute myeloblastic leukemia cases, whereas only the JAK2 wild-type allele was detected in the other 25. Nineteen of 20 cases with adequate bone marrow samples available for molecular examination demonstrated concordant JAK2 genotypes. Laser-capture microdissection was then used to enrich the EMH and non-EMH splenic cell fractions, confirming that the mutant alleles specifically originated from the EMH cells. Furthermore, megakaryocytes in the JAK2(V617F)-positive splenectomy specimens expressed higher levels of Bcl-xL, an antiapoptotic protein and downstream target of the JAK2/STAT5 pathway. Thus, JAK2(V617F) is frequently present in splenic EMH cells associated with CMPD, but it is rarely identified in splenic EMH cells associated with other myeloid disorders. Our results indicate that the precursor cells leading to extramedullary hematopoietic expansion in CMPD most likely originate from the transformed bone marrow clone. Also, dysregulation of downstream pathways such as Bcl-xL may be important to CMPD disease pathogenesis in the spleen.
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PMID:The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders. 1764

This study evaluates changes in genetic loci of chronic myeloid disorders using loss of heterozygosity (LOH) techniques. We present the combined results of three experiments. First, examination of a panel of genetic loci in groups of myeloproliferative disorders was evaluated. The second experiment involved microdissection of megakaryocytes from myeloproliferative disorders and comparison of their genetic changes to surrounding neoplastic marrow elements. Finally, we compared results of LOH studies of myeloproliferative disorders to those of myelodysplastic syndromes and chronic myelomonocytic leukemia. A total of 41 bone marrow biopsies were evaluated. Twenty-seven were myeloproliferative disorders (11 chronic idiopathic myelofibrosis, 11 essential thrombocythemia, 5 polycythemia vera). The remaining cases consisted of myelodysplastic syndromes (total=5; RAEB-1=2; RAEB-2=2; MDS, not otherwise specified=1) and chronic myelomonocytic leukemia (n=8). The abnormalities in myeloproliferative disorders were distributed as follows: D7S2554-4/14 (5/14); D8S263-4/15 (5/15); D9S157-5/15 (5/15); D9S161-7/17 (6/17); D13S319-5/14 (4/14); TP53-5/16 (5/16); D20S108-4/15 (4/15). In 75% cases diagnosed as essential thrombocythemia (6/8), both cases of polycythemia vera (2/2), and 29% cases of chronic idiopathic myelofibrosis (2/7), there were genetic differences between the megakaryocytes and the surrounding marrow. These results suggest that in some cases, megakaryocytes have different clonal abnormalities than surrounding hematopoietic tissue. The genetic profiles of myeloproliferative disorders had several differences from those of myelodysplastic syndromes. Although different from both, chronic myelomonocytic leukemia appeared more similar to myeloproliferative disorders using these techniques.
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PMID:Loss of heterozygosity identifies genetic changes in chronic myeloid disorders, including myeloproliferative disorders, myelodysplastic syndromes and chronic myelomonocytic leukemia. 1770 56

Extramedullary hematopoiesis occurs in patients with a variety of hematologic diseases, and the spleen is a common site. Extramedullary hematopoiesis is very common in chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases. The pathogenesis of extramedullary hematopoiesis is unknown. Using JAK2 V617F mutation as a molecular marker, we assessed paired spleen and bone marrow samples of 15 patients with various types of chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases. The diagnosis was chronic idiopathic myelofibrosis (n=8), polycythemia vera (n=3), and chronic myelomonocytic leukemia (n=4). DNA was extracted from fixed, paraffin-embedded tissue and assessed for JAK2 V617F by real-time polymerase chain reaction assay followed by melting curve analysis. Concordant JAK2 mutation was detected in the paired samples in 7 patients. A discordant result with JAK2 V617F found in the spleen but not bone marrow was noted in 1 patient. These results indicate that extramedullary hematopoiesis in patients with chronic myeloproliferative diseases and myeloproliferative/myelodysplastic diseases is a clonal process and lend support to the theory that the cells of extramedullary hematopoiesis are carried from the bone marrow.
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PMID:Janus kinase 2 V617F mutation is detectable in spleen of patients with chronic myeloproliferative diseases suggesting a malignant nature of splenic extramedullary hematopoiesis. 1770 84

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
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PMID:Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. 1938 8

The chromosomal abnormality der(9)t(1;9)(q11;q34) is a rare occurrence in patients with hematologic malignancies. As far as we know, only 3 cases of acute myeloid leukemia, 1 case of polycythemia vera, and 1 case of multiple myeloma with this derivative chromosome have been reported in the literature. Here we report the first case of der(9)t(1;9)(q11;q34) in a patient with chronic myelomonocytic leukemia (CMML). A 45-yr-old man was brought to our hospital for evaluation of pancytopenia and monocytosis. The patient's persistent monocytosis in peripheral blood and his bone marrow findings were consistent with the diagnosis of CMML. Chromosome study results repeatedly showed 46,XY,der(9)t(1;9)(q11;q34). In addition, the BCR/ABL fluorescent in situ hybridization (FISH) pattern of the interphase cells was interpreted as: "nuc ish(ABL, BCR) x 2[292/300]," consistent with the normal signal patterns found in 97% of the nuclei examined. For further evaluation, multi-color FISH (mFISH) analysis was performed and it showed the distinct unbalanced derivative chromosome der(9)t(1;9)(q11;q34) in 5 metaphase cells analyzed. Not only does this show an extraordinary type of trisomy 1q, but it reveals a rare recurrent case of der(9)t(1;9)(q11;q34) in patients with monocytic-lineage leukemia. Further studies are needed to evaluate the prognosis, survival, and treatment response of such patients with der(9)t(1;9)(q11;q34).
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PMID:Chronic myelomonocytic leukemia with der(9)t(1;9)(q11;q34) as a sole abnormality. 1966 17

The chronic myeloproliferative disorders (MPDs) include the spectrum of clonal hematopoietic stem cell disorders whose phenotype derive from the primary cell expanded in a proliferative state. The MPDs (which include polycythemia vera (PV), essential thrombocythemia (ET), chronic eosinophilic leukemia (CEL), primary myelofibrosis (PMF), chronic myelomonocytic leukemia (CMML), and systemic mast cell disease (SMCD)) exclude chronic myeloid leukemia (CML) because of the pathognomic importance of the BCR-ABL translocation for the diagnosis and treatment of this disorder with imatinib mesylate. Empiric use of imatinib mesylate against the spectrum of BCR-ABL negative MPDs has had mixed results. Significant benefits were obtained when empiric use of imatinib in CEL and CMML led to significant clinical benefit and the discovery of the role of rearrangements of the platelet derived growth factor receptor -alpha (PDGFRa-FIP1L1 in CEL and SMCD) and -beta (PDGFRb through TEL-PDGFRb) for CMML). Empiric use of imatinib in PMF has been disappointing, and in PV quite modest. Although next generation Abelson kinase inhibitors such as dasatinib or nilotinib may expand the role for these agents in MPDs, targeted inhibition of the mutant kinase JAK2(V617F) is more likely to make significant therapeutic gains in the classic MPDs of PV, ET, and PMF.
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PMID:Imatinib and tyrosine kinase inhibition, in the management of BCR-ABL negative myeloproliferative disorders. 1970 23

The activating mutation of JAK2, V617F, has been found as a frequent mutation in myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). This mutation is observed not only in MPNs, but also in chronic myelomonocytic leukemia, myelodysplastic syndrome and acute myeloid leukemia (AML). We report a case of myeloid sarcoma and myelofibrosis, followed by secondary AML, with detection of homozygous JAK2 V617F mutation. This report describes the first case of myeloid sarcoma with JAK2 V617F mutation and implication of its progression to AML.
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PMID:A case of myeloid sarcoma with correlation to JAK2V617F mutation, complicated by myelofibrosis and secondary acute myeloid leukemia. 2204 74

There is no single category in the fourth edition (2008) of the World Health Organization (WHO) classification of myeloid neoplasms that encompasses all of the diseases referred to by some authors as the myeloproliferative neoplasm (MPN) "variants." Instead, they are considered as distinct entities and are distributed among various subgroups of myeloid neoplasms in the classification scheme. These relatively uncommon neoplasms do not meet the criteria for any so-called "classical" MPN (chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, or essential thrombocythemia) and, although some exhibit myelodysplasia, none meets the criteria for any myelodysplastic syndrome (MDS). They are a diverse group of neoplasms ranging from fairly well-characterized disorders such as chronic myelomonocytic leukemia to rare and thus poorly characterized disorders such as chronic neutrophilic leukemia. Recently, however, there has been a surge of information regarding the genetic infrastructure of neoplastic cells in the MPN variants, allowing some to be molecularly defined. Nevertheless, in most cases, correlation of clinical, genetic, and morphologic findings is required for diagnosis and classification. The fourth edition of the WHO classification provides a framework to incorporate those neoplasms in which a genetic abnormality is a major defining criterion of the disease, such as those associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1, as well as for those in which no specific genetic defect has yet been discovered and which remain clinically and pathologically defined. An understanding of the clinical, morphologic, and genetic features of the MPN variants will facilitate their diagnosis.
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PMID:World health organization classification, evaluation, and genetics of the myeloproliferative neoplasm variants. 2216 42

We investigated 15,542 patients with suspected BCR-ABL1- negative myeloproliferative or myelodysplastic/myeloproliferative neoplasm (including 359 chronic myelomonocytic leukemia) by a molecular marker set. JAK2V617F was detected in the suspected categories as follows: polycythemia vera 88.3%, primary myelofibrosis 53.8%, essential thrombocythemia 50.2%, and not further classifiable myeloproliferative neoplasms 38.0%. JAK2 exon 12 mutations were detected in 40.0% JAK2V617F-negative suspected polycythemia vera, MPLW515 mutations in 13.2%JAK2V617F-negative primary myelofibrosis and 7.1% JAK2V617F-negative essential thrombocythemia. TET2 mutations were distributed across all entities but were most frequent in suspected chronic myelomonocytic leukemia (77.8%). CBL mutations were identified in suspected chronic myelomonocytic leukemia (13.9%), primary myelofibrosis (8.0%), and not further classifiable myeloproliferative neoplasm (7.0%). This leads to a stepwise workflow for suspected myeloproliferative neoplasms starting with JAK2V617F and investigating JAK2V617F-negative patients for JAK2 exon 12 or MPL mutations, respectively. In cases in which a myeloproliferative neoplasm cannot be established, analysis for TET2, CBL and EZH2 mutations may be indicated.
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PMID:Molecular analyses of 15,542 patients with suspected BCR-ABL1-negative myeloproliferative disorders allow to develop a stepwise diagnostic workflow. 2251 94


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