Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major vault lung resistance protein LRP is a cytoplasmic protein involved in drug resistance, especially in acute myeloid leukemia. We looked for LRP overexpression, using immunocytochemistry with LRP 56 monoclonal antibody, on marrow slides from 41 cases of myelodysplastic syndromes (MDS). LRP overexpression (LRP+) was defined by expression of LRP 56 in at least 20% of marrow blasts. LRP overexpression was seen in 19 (46%) cases. Concordant results between LRP overexpression and P-glycoprotein (PGP) expression were seen in 66% of the cases (p = 0.03), and discordant results (LRP+ and PGP-, or LRP- and PGP+) in 33% of the cases. No correlation was seen between LRP overexpression and FAB type, karyotype, CD34, p53 expression and bcl2 overexpression in blasts. Furthermore, in the 18 cases treated with anthracycline-AraC intensive chemotherapy and the 7 cases treated with low dose AraC, the response rate was not significantly different in LRP+ and LRP- patients. Survival was also similar in LRP+ and LRP- patients. In conclusion, LRP overexpression is probably more frequent in MDS than in de novo AML and, as in AML, is only partially correlated with PGP expression. In our experience, however, LRP was not a prognostic factor for response to chemotherapy and survival in MDS.
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PMID:Expression of lung resistance protein and correlation with other drug resistance proteins and outcome in myelodysplastic syndromes. 964 68

Myeloproliferative disorders (MPD) represent a subcategory of hematological malignancies and are characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leucocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). At present, these four disorders are referred to as 'classic' MPD and are distinguished from a spectrum of other MPD-like clinicopathologic entities that are operationally classified as 'atypical' MPD. The oncogenic mutations(s) in classic MPD are unknown except for CML, which is associated with an activating mutation (Bcr/Abl) of the gene encoding for the Abl cytoplasmic protein kinase (PTK). In the last 3 months, a somatic point mutation of JAK2 (JAK2(V617F)), the gene encoding for another cytoplasmic PTK was reported in the majority of patients with PV and approximately half of those with either ET or MMM. The same mutation was also found in a small number of patients with either atypical MPD or the myelodysplastic syndrome but not in normal controls, germline tissue including T lymphocytes, and patients with secondary erythrocytosis. In vitro, JAK2(V617F) was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell lines. In vivo, murine bone marrow transduced with a retrovirus containing JAK2(V617F) induced erythrocytosis in the transplanted mice. Taken together, these observations suggest that JAK2(V617F) is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD.
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PMID:JAK2 in myeloproliferative disorders is not just another kinase. 1597 Jul 5

Janus kinase 2 (JAK2) is a cytoplasmic protein-tyrosine kinase that catalyzes the transfer of the gamma-phosphate group of adenosine triphosphate to the hydroxyl groups of specific tyrosine residues in signal transduction molecules. JAK2 mediates signaling downstream of cytokine receptors after ligand-induced autophosphorylation of both receptor and enzyme. The main downstream effectors of JAK2 are a family of transcription factors known as signal transducers and activators of transcription (STAT) proteins. The myeloproliferative disorders (MPD), a subgroup of myeloid malignancies, are clonal stem cell diseases characterized by an expansion of morphologically mature granulocyte, erythroid, megakaryocyte, or monocyte lineage cells. Among the traditionally classified MPD, the disease-causing mutation has been delineated, thus far, for only chronic myeloid leukemia (ie, bcr/abl). In the past 3 months, 7 different studies have Independently described a close association between an activating JAK2 mutation (JAK2V617F) and the classic bcr/abi-negative MPD (ie, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia) as well as the less frequent occurrence of the same mutation in both atypical MPD and the myelodysplastic syndrome. The particular finding is consistent with previous observations that have implicated the JAK/STAT signal transduction pathway in the pathogenesis of bcr/abl-negative MPD, Including the phenotype of growth factor independence and/or hypersensitivity. The current article summarizes this new information and discusses its implications for both classification and diagnosis of MPD.
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PMID:The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis. 1600 2