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

Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-I studies regarding efficacy and potential toxicity of these compounds have already been reported.
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PMID:Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders. 1852 25

Atypical chronic myeloid leukemia (aCML) as defined by the WHO classification is a rare hematopoietic stem cell disorder, which shows both myeloproliferative as well as myelodysplastic features. Because of the presence of neutrophilic leukocytosis, aCML may resemble chronic myelogenous leukemia. However, in contrast with the latter, aCML lacks a Philadelphia chromosome or the BCR/ABL fusion gene. The molecular pathogenesis of aCML and its relationship to other myeloproliferative neoplasms is unknown. To clarify these points, the presence of JAK2 V617F was examined by a retrospective analysis of archival specimens obtained from two large medical institutions. Paraffin-embedded bone marrow (BM) trephines and clot sections were examined by an allele-specific TaqMan PCR suitable for use with decalcified tissue. Fifty-nine cases of Philadelphia (Ph) chromosome negative chronic myeloproliferative neoplasms (CMPN) and normal bone marrows (BM) served as controls. None of the nine amplifiable cases of aCML and none of the normal BM controls showed a JAK2 V617F mutation, in contrast to 45/59 (76%) of the Ph chromosome negative CMPN cases. Atypical CML should therefore be considered as a JAK2 negative chronic myeloid neoplasm that remains properly categorized, alongside chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, within the WHO group of myelodysplastic/myeloproliferative neoplasms.
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PMID:Atypical chronic myeloid leukemia as defined in the WHO classification is a JAK2 V617F negative neoplasm. 1942 35

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.
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PMID:Evolutional change of karyotype with t(8;9)(p22;p24) and HLA-DR immunophenotype in relapsed acute myeloid leukemia. 1859 80

Myeloproliferative disorders (MPDs), typified by robust marrow and extramedullary hematopoiesis, have a propensity to progress to acute leukemia. Although the hematopoietic stem cell (HSC) origin of MPDs was suggested over 30 years ago, only recently the HSC-specific effects of MPD molecular mutations have been investigated. The pivotal role of BCR-ABL in chronic myeloid leukemia (CML) development provided the rationale for targeted therapy, which greatly reduced mortality rates. However, BCR-ABL inhibitor-resistant CML HSCs persist that may be a reservoir for relapse. This has provided the impetus for investigating molecular mechanisms governing the production of recalcitrant HSC. Comparatively little was known about the molecular events driving BCR-ABL-negative MPDs until seminal studies revealed that a large proportion of MPD patients harbor a JAK2-activating point mutation, JAK2V617F. Although JAK2 activation appears to be central to BCR-ABL-negative MPD pathogenesis, its effects may be cell type and context specific. Recent evidence suggests that acquired mutations misdirect differentiation and survival of the MPD-initiating stem cell resulting in the production of aberrant self-renewing progenitors that subvert the microenvironment leading to leukemia stem cell generation and leukemic transformation. Thus, combined therapies targeting aberrant molecular pathways may be required to redirect miscreant MPD stem cells.
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PMID:Miscreant myeloproliferative disorder stem cells. 1892 36

Chronic myeloid leukemia (CML) represents the first human malignancy successfully treated with a tyrosine kinase inhibitor (TKI; imatinib). However, early relapses and the emergence of imatinib-resistant disease are problematic. Evidence suggests that imatinib and other inhibitors may not effectively eradicate leukemic stem/progenitor cells, and that combination therapy directed to complimentary targets may improve treatment. Abelson helper integration site 1 (Ahi-1)/AHI-1 is a novel oncogene that is highly deregulated in CML stem/progenitor cells where levels of BCR-ABL transcripts are also elevated. Here, we demonstrate that overexpression of Ahi-1/AHI-1 in murine and human hematopoietic cells confer growth advantages in vitro and induce leukemia in vivo, enhancing effects of BCR-ABL. Conversely, RNAi-mediated suppression of AHI-1 in BCR-ABL-transduced lin(-)CD34(+) human cord blood cells and primary CML stem/progenitor cells reduces their growth autonomy in vitro. Interestingly, coexpression of Ahi-1 in BCR-ABL-inducible cells reverses growth deficiencies exhibited by BCR-ABL down-regulation and is associated with sustained phosphorylation of BCR-ABL and enhanced activation of JAK2-STAT5. Moreover, we identified an AHI-1-BCR-ABL-JAK2 interaction complex and found that modulation of AHI-1 expression regulates phosphorylation of BCR-ABL and JAK2-STAT5 in CML cells. Importantly, this complex mediates TKI response/resistance of CML stem/progenitor cells. These studies implicate AHI-1 as a potential therapeutic target downstream of BCR-ABL in CML.
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PMID:AHI-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. 1893 34

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPNs) include BCR-ABL in chronic myelogenous leukemia (CML) and a spectrum of PDGFRA/B mutant proteins that are products of intra- (eg, FIP1L1-PDGFRA) or interchromosomal (eg, ETV6-PDGFRB) gene fusions. Other MPN-relevant putative oncogenes that are awaiting therapeutic validation, include JAK2 and MPL mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF); KITD816V and other KIT mutations in systemic mastocytosis, and FGFR1 rearrangements associated with the 8p11 leukemia/lymphoma syndrome. The current review focuses on mutant molecules of interest in classic MPNs (ie, CML, PV, ET, and PMF) in the context of their value as drug targets.
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PMID:Oncogenic signals as treatment targets in classic myeloproliferative neoplasms. 1914 89

The key molecular events in the pathogenesis of myeloproliferative disorders (MPD) have been poorly defined to date, except the case of chronic myeloid leukaemia with the associated rearranged gene bcr/abl. In recent years, a number of different studies described the detection of JAK2 V617F mutation in haematopoietic cells from polycythemia vera patients and other MPDs, which indicates that it plays an important role in the pathogenesis of MPDs. In this review, the JAK2 V617F point mutation and its detection methods, its clinical correlations with MPDs and other malignant hepatopathies were summarized.
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PMID:[Advance of study on JAK2 V617F in myeloproliferative disorders -- review]. 1923 88

The association of V617F JAK2 expression levels with disease behavior has not been studied in patients with nonchronic myelogenous leukemia (CML) myeloproliferative disease (MPD). We found plasma levels of total JAK2 mRNA to be higher in patients with non-CML MPD (n=175) than in CML patients (n=45) and normal controls (n=58) (each P<0.001). Overall survival was studied in 68 patients and showed positive correlation with levels of total and mutant JAK2 mRNA in patients with the V617F mutation, but not those without the mutation. These findings suggest that total JAK2 expression levels play a role in the biology of the disease in V617F-positive patients, and a therapy aiming at downmodulating the expression of the total JAK2 mRNA should be considered. In conclusion, we studied JAK2 total and V6217F mutant mRNA levels in plasma. We show high levels of JAK2 expression in MPD patients and these levels correlate with survival.
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PMID:Plasma levels of JAK2 mRNA in patients with chronic myeloproliferative diseases with and without V617F mutation: implications for prognosis and disease biology. 1925 49

According to the 2008 World Health Organization classification system for hematologic malignancies, the myeloproliferative neoplasms (MPN) include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, mastocytosis, chronic eosinophilic leukemia-not otherwise specified, chronic neutrophilic leukemia, and "MPN, unclassifiable." All of these clinicopathologic entities are characterized by stem cell-derived clonal myeloproliferation, and their phenotypic diversity is ascribed to the occurrence of distinct oncogenic events. In the last 4 years, new JAK2 and MPL mutations have been added to previously described ABL and KIT mutations as molecular markers of disease in MPN. These discoveries have markedly simplified the approach to clinical diagnosis and have also provided molecular targets for the development of small-molecule drugs. In the current article, the authors provide a clinically oriented overview of MPNs in terms of their molecular pathogenesis, classification, diagnosis, and management.
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PMID:Advances in understanding and management of myeloproliferative neoplasms. 1936 82

Myeloproliferative disorders (MPDs) are clonal malignancies that arise from hematopoietic progenitors and characterized by overproduction of mature, functional blood cells. These disorders can be broadly characterized into Philadelphia chromosome-positive (Ph(+)) or negative (Ph(-)) genetic groupings. Chronic myeloid leukemia (CML) is a Ph(+) MPD that is defined on the basis of its molecular lesion, the BCR-ABL fusion gene. Inhibitors directed at the constitutive kinase activity of BCR-ABL have been shown to be disease modifying in CML and have dramatically altered the standard of care for this leukemia. The three main Ph(-) MPDs are polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The key features of these Ph(-) MPDs are an increased red blood cell mass in PV, a high platelet count in ET and bone marrow fibrosis in PMF, respectively. These disorders also share many clinical features such as long clinical course, increased risk for thrombosis, hemorrhage and elevated risk of leukemic transformation. Interest in these disorders has been ignited by the recent discovery of activating mutations in the tyrosine kinase gene, JAK2, in the predominance of Ph(-) MPD patients and has highlighted JAK2 as a therapeutic intervention point for drug discovery efforts with selective kinase inhibitors. This review will focus on the comparison of Ph(+) and Ph(-) MPDs, drug discovery and development efforts targeting these disorders, and will assess the new opportunities for targeted therapies for these diseases.
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PMID:Kinase drug discovery approaches in chronic myeloproliferative disorders. 1942 Nov 40


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