Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development and function of hematopoietic cells depends on complex signaling pathways that are mediated by numerous cytokines and their receptors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is prominent both in normal hematopoiesis and in hematological malignancies. STATs are phosphorylated on tyrosine residues via JAK kinases and on serine residues by a variety of serine/threonine kinases. STATs then dimerize, translocate to the nucleus and bind DNA, initiating the transcription of target genes. STAT proteins mediate cell growth, differentiation, apoptosis, transformation, and other fundamental cell functions. Recently, mutations in the JAK2 gene driving the proliferation of the neoplastic clone have been identified in myeloproliferative disorders. In addition constitutive activation of the JAK-STAT pathway has been reported in various types of leukemias such as acute myelogenous leukemia, T-LGL leukemia, and multiple myeloma. This review describes the pathophysiological role of this pathway in hematological malignancies and the potential benefits of JAK-STAT inhibition.
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PMID:The JAK-STAT pathway: a therapeutic target in hematological malignancies. 1716 72

Recent surveys have indicated that thromboembolic complications are at least as common in hematologic malignancies, if not more frequent, than in solid tumors. The pathogenesis of thrombosis is similar to that in solid tumors, but with additional factors unique in several forms of hematologic malignancies, as seen in acute promyelocytic leukemia, myeloma, and myeloproliferative disorders. Likewise, the factors contributing to bleeding are similar to those seen in solid tumors, with the exception of a higher frequency of thrombocytopenia.
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PMID:Incidence and pathogenesis of thrombosis in hematologic malignancies. 1752 87

The aim of the present study was to identify trends in numbers of European patients treated with autologous and allogeneic haematopoietic stem cell transplantation (HSCT) as well as to provide anticipated transplant rates for the upcoming years. The following indications were considered: haematological malignancies (acute leukaemias, myeloproliferative disorders, lymphoproliferative disorders and multiple myeloma), solid tumours and non-malignant diseases. Numbers of patients treated from 1990 to 2004 were extracted from the European Group for Blood and Marrow Transplantation database, extrapolated to 2012 using mathematic models and adjusted to the literature study and expert opinion. In Europe, a 13% raise in HSCT utilisation is to be expected from 2005 to 2010, mostly due to the growing application of reduced-intensity conditioning regimens followed by allogeneic HSCT. Growing transplant rates are likely to exert health expenditure budgets and put pressure on health care providers and health insurers in Europe. Therefore, the rapid expansion would ideally imply a simultaneous increase in HSCT budgets.
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PMID:Stem cell transplantation in Europe: trends and prospects. 1791

A 65-year-old male patient initially presented with a penile tumour, identified as myeloid sarcoma. Subsequent bone marrow investigation revealed the presence of a synchronous plasma cell myeloma, without any evidence of a bone marrow-based myeloproliferative disorder. Although the course of both neoplasms was progressive, with increasing bone marrow involvement by the plasma cell myeloma and cutaneous dissemination of the myeloid sarcoma, both neoplasms remained confined to their original tissue compartments. Different biology of both tumours, including markedly divergent response to therapies, contributed to a significant clinical dilemma and finally to the patient demise 16 months after the presentation. While the association of plasma cell myeloma and various myeloid leukaemias is well documented, this is a first report of simultaneous occurrence of a myeloma and a myeloid sarcoma.
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PMID:[Concomitant myeloid sarcoma and plasma cell myeloma--case report of a hitherto undescribed association of two neoplasms]. 1804 42

Flow cytometric immunophenotyping remains an indispensable tool for the diagnosis, classification, staging, and monitoring of hematologic neoplasms. The last 10 years have seen advances in flow cytometry instrumentation and availability of an expanded range of antibodies and fluorochromes that have improved our ability to identify different normal cell populations and recognize phenotypic aberrancies, even when present in a small proportion of the cells analyzed. Phenotypically abnormal populations have been documented in many hematologic neoplasms, including lymphoma, chronic lymphoid leukemias, plasma cell neoplasms, acute leukemia, paroxysmal nocturnal hemoglobinuria, mast cell disease, myelodysplastic syndromes, and myeloproliferative disorders. The past decade has also seen refinement of the criteria used to identify distinct disease entities with widespread adoption of the 2001 World Health Organization (WHO) classification. This classification endorses a multiparametric approach to diagnosis and outlines the morphologic, immunophenotypic, and genotypic features characteristic of each disease entity. When should flow cytometric immunophenotyping be applied? The recent Bethesda International Consensus Conference on flow cytometric immunophenotypic analysis of hematolymphoid neoplasms made recommendations on the medical indications for flow cytometric testing. This review discusses how flow cytometric testing is currently applied in these clinical situations and how the information obtained can be used to direct other testing.
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PMID:Flow cytometric immunophenotyping for hematologic neoplasms. 1819 45

While there is good evidence for a protective effect of aspirin against occlusive vascular events in individuals with arterial disease, its role in preventing venous thromboembolism (VTE) is unclear. In this article we review the role of aspirin and other antiplatelet drugs in prevention of venous thromboembolism in surgical patients, high risk medical patients requiring aspirin for other reasons, patients with myeloproliferative disorders, long distance travellers and patients receiving treatment with the IMiD class of drugs. Overall, data from the PEP study and Anti-Platelet Trialists' systematic review show that aspirin reduces the risk of VTE by around 25% in high risk surgical patients. Data from retrospective and before/after studies also suggest efficacy in reducing VTE in myeloma patients on IMiD drugs in combination with dexamethasone or chemotherapy. However, there has been no direct comparison with coumarins or heparin to indicate that aspirin is the optimal form of thromboprophylaxis. In patients who require aspirin because of high risk of arterial vascular occlusion (including patients with polycythaemia vera and essential thrombocythaemia), the additional small reduction in VTE risk is an added benefit with no additional risk associated. There is no evidence for a role of aspirin in prevention of travel-related thrombosis. At present there is no clear evidence that aspirin is the drug of choice for the prevention of VTE in any patient group.
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PMID:Aspirin and other antiplatelet drugs in the prevention of venous thromboembolism. 1822 35

Previous descriptions of familial myeloma have been mainly of Caucasian families. We report here eight African American families with familial multiple myeloma and monoclonal gammopathy identified over a 30 year period. Six patients with multiple myeloma (MM) and two with monoclonal gammopathy of unknown significance (MGUS) reported a family history of MM or had family members with MGUS found on screening. A pedigree compiled for each family included a history of other cancers. In the eight families, 21 of 58 first degree relatives had a plasma cell dyscrasia including 12 MM, eight MGUS, and one amyloidosis patient(s). The age of the MM patients ranged from 50 to 78 years (median 61 years). Four families had two members with MM, including one mother-son and three sibling pairs. Two MM families each had two additional first degree relatives with MGUS, with three generations involved in one family. Anticipation was suggested in two families with parent-child pairs with monoclonal gammopathy. The eight pedigrees had 66 members, 21 of whom had a diagnosis of cancer, including non-Hodgkin lymphoma and Hodgkin disease, or a clonal myeloproliferative disorder other than MM. Although the mode of genetic transmission and anticipation cannot be confirmed due to the small sample size, the increased number of MM and MGUS family members suggests underlying genetic susceptibility factors for plasma cell dyscrasias and possibly for other cancers in these families.
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PMID:Familial myeloma and monoclonal gammopathy: a report of eight African American families. 1903 64

The discovery of the JAK2V617F mutation followed by the discovery of JAK2 exon 12 and MPLW515 mutations has completely modified the understanding, diagnosis, and management of the classic myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nonetheless, genetic defects have not yet been identified in about 40% of ET and PMF. There is now strong evidence that these mutations are the oncogenic events that drive these disorders and are responsible for most biologic and clinical abnormalities. In addition, there are convincing data indicating that the number of JAK2V617F copies (homozygosity vs. heterozygosity) is important in explaining how a single mutation can be associated with several disorders. However, it is still uncertain whether these mutations are sufficient to explain the full development, heterogeneity, and progression of MPD, or if other genetic or epigenetic events are also necessary. In this review, we discuss different hypothetical models of MPD pathogenesis supported by recent findings. Further characterization of the molecular events operating in these disorders will be essential in fully understanding their pathogenesis and in developing new therapeutic approaches.
Clin Lymphoma Myeloma 2009
PMID:Molecular and genetic bases of myeloproliferative disorders: questions and perspectives. 1977 61

Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.
Clin Lymphoma Myeloma 2009
PMID:JAK2 inhibitors: A reality? A hope? 1977 62

We report the emergence of chronic myelogenous leukemia (CML) in a patient with JAK2V617F-positive polycythemia vera after 15 years of phlebotomy. The polycythemia vera clinical and molecular findings were suppressed at the time of CML diagnosis, only to re-emerge after the leukemia was successfully treated with imatinib. We explored the potential association between myeloproliferative disorders and CML in the context of the current literature and found a higher-than-expected coincidence based on known epidemiologic data for each specific condition. We hypothesize that myeloproliferative disorder (JAK2V617F or molecular events that cause JAK2V617F) is a risk factor for CML (BCR-ABL translocation). Because of therapeutic implications, clinicians should be aware that the conditions co-occur more frequently than once thought.
Clin Lymphoma Myeloma 2009 Oct
PMID:Emergence of chronic myelogenous leukemia from a background of myeloproliferative disorder: JAK2V617F as a potential risk factor for BCR-ABL translocation. 1985 50


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