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)

The treatment of hematologic malignancies has been based for many years on chemotherapy and possibly, for the more aggressive forms, stem cell transplantation. In 2001, the signal transduction inhibitor 571 (STI571, imatinib mesylate) was reported to have striking effects in chronic myeloid leukaemia patients. Since then, imatinib became the first molecular-targeted agent approved for the treatment of human cancer and was later on demonstrated to be effective in other malignancies, such as Philadelphia positive acute lymphoid leukemia, hypereosinophilic syndromes, gastrointestinal stromal tumours and more recently, systemic mastocytosis and other myeloprolipherative disease-carrying platelet-derived growth factor receptor abnormalities. In this article, the authors review the evidence which led to imatinib approval in the treatment of several of the above mentioned diseases.
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PMID:Imatinib mesylate in the treatment of hematologic malignancies. 1791 51

Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.
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PMID:Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2. 1791 67

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

Myeloproliferative syndromes (MPS) are clonal proliferation of hematopoietic progenitor cells characterized by proliferation of 1 or a few cell lines such as granulocytic, erythroid, megakaryocytic or mastocytic. These syndromes include: chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myelofibrosis, chronic eosinophilic leukemia/hypereosinophilic syndrome, chronic neutrophilic leukemia and systemic mastocytosis. Diagnosis of MPS is often difficult due to need of differential diagnosis with reactive proliferation caused by primarily non-hematological factors. Differentiation of individual MPS forms is also difficult because of overlapping of particular clinical or laboratory adnormalities. Discovery of specific molecular aberrations in the last few years facilitates diagnostic procedures. The discovered gene mutations or their fusions are associated with production of proteins possessing tyrosine kinase properties. These discoveries resulted in the successful introduction of the targeted therapy with tyrosine kinase inhibitors in the recent years.
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PMID:Myeloproliferative syndromes: diagnosis and therapeutic options. 1920 55

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

The mast cell has been associated with fibrosis in many different tissues, organs, and different disease processes including hematopoietic malignancies. Mast cells are often increased in the bone marrow of patients with primary bone marrow disorders, and patients with systemic mastocytosis often have a second concomitant neoplastic disease of the bone marrow. The goals of the current study were to determine the role the mast cell has in the pathogenesis of myeloproliferative neoplasms (MPN) and to correlate the mast cell burden with the degree of reticulin fibrosis. We used computer-assisted image analysis of bone marrow core biopsies stained for mast cell tryptase from patients with myeloproliferative neoplasms [31 cases: 12 chronic myelogenous leukemia (CML), 6 primary myelofibrosis (PMF), 4 essential thrombocythemia (ET), 4 polycythemia vera (PV), and 5 chronic myeloproliferative disorder, unclassifiable (CMPD-U)]. Although the number of cases of some subtypes of MPN was small, the results suggested that PMF and ET each had significantly more mast cells than both CML and control cases (P<0.01 and 0.05, respectively, Mann-Whitney test). CMPD-U and PV showed no significant differences from the control cases, but the CML cases had significantly fewer mast cells than our control cases (P=0.02, Mann-Whitney test). In addition, the quantity of mast cells seen in the bone marrows of MPN patients correlated with reticulin fibrosis (P=0.04, Mann-Whitney test). Our studies highlight the different mast cell quantities in different myeloproliferative neoplasms and suggest a direct role for the mast cell in intramedullary fibrosis. Further studies are warranted to confirm our observation and to study the mechanisms by which mast cells contribute to fibrosis in the MPN setting.
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PMID:Mast cell burden and reticulin fibrosis in the myeloproliferative neoplasms: a computer-assisted image analysis study. 1944 6

The 2008 WHO classification system for hematological malignancies is comprehensive and includes histology and genetic information. Myeloid neoplasms are now classified into five categories: acute myeloid leukemia, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN, and myeloid and/or lymphoid malignancies associated with eosinophilia and PDGFR or FGFR1 rearrangements. MPN are subclassified into eight separate entities: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, systemic mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and unclassifiable MPN. The diagnosis of chronic myelogenous leukemia requires the presence of BCR-ABL1, while its absence is required for all other MPN. Additional MPN-associated molecular markers include mutations of JAK2, MPL, TET2 and KIT. JAK2 V617F is found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and is, therefore, useful as a clonal marker in those settings. The diagnostic utility of MPL and TET2 mutations is limited by low mutational frequency. In systemic mastocytosis, presence of KIT D816V is expected but not essential for diagnosis. Chronic eosinophilic leukemia not otherwise specified should be distinguished from both PDGFR-rearranged or FGFR1-rearranged neoplasms and hypereosinophilic syndrome. We discuss histologic, cytogenetic and molecular changes in MPN and illustrate their integration into practical diagnostic algorithms.
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PMID:Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. 1980 46

Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying myeloid malignancy. The World Health Organization classification system for hematologic malignancies recognizes 2 distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor alpha/beta or fibroblast growth factor receptor 1. Clonal eosinophilia might also accompany other World Health Organization-defined myeloid malignancies, including chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and systemic mastocytosis. Hypereosinophilic syndrome, a subcategory of idiopathic eosinophilia, is defined by the presence of a peripheral blood eosinophil count of 1.5 x 10(9)/L or greater for at least 6 months (a shorter duration is acceptable in the presence of symptoms that require eosinophil-lowering therapy), exclusion of both secondary and clonal eosinophilia, evidence of organ involvement, and absence of phenotypically abnormal and/or clonal T lymphocytes. The presence of the latter defines lymphocytic variant hyper eosinophilia, which is best classified under secondary eosinophilia. In the current review, we provide a simplified algorithm for distinguishing the various causes of clonal and idiopathic eosinophilia and discuss current therapy, including new drugs (imatinib mesylate, alemtuzumab, and mepolizumab).
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PMID:Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. 2005 13

Myeloproliferative neoplasms (MPNs; formerly chronic myeloproliferative disorders) are a class of myeloid hematologic malignancies that represent a stem cell-derived expansion of 1 or more hematopoietic cell lineages. The current 2008 World Health Organization system recognizes 8 types of MPN: chronic myelogenous leukemia, chronic neutrophilic leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic eosinophilic leukemia, mastocytosis, and myeloproliferative neoplasm, unclassifiable. This review summarizes the salient characteristics of the MPNs, with emphasis on recent developments in the molecular pathophysiology and therapeutic monitoring of these disorders.
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PMID:Molecular pathology of myeloproliferative neoplasms. 2023 14

Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1(+) CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of altering the acetylation status of both histone and non-histone proteins, thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation, differentiation, immune responses, angiogenesis and survival. Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the pro-apoptotic effects on MPN cells. This review provides a review of pre-clinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNs.
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PMID:Deactylase inhibition in myeloproliferative neoplasms. 2112 42


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