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

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-alpha and interleukin-1beta from MDS BM-mononuclear cells and BM-stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.
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PMID:Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. 1151 Apr 70

Increased angiogenesis is important in the pathophysiology of solid tumors. Recent studies show that angiogenesis and angiogenic factors play an important role in hematological malignancies. Both acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are associated with a substantial increase in vascularity in the bone marrow as well as increased levels of various angiogenic factors including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiogenin, angiopoietin-1, platelet-derived growth factor, hepatocyte growth factor, epidermal growth factor, tumor necrosis factor-alpha, and transforming growth factor-alpha and transforming growth factor-beta. Most of these angiogenic factors appear to be secreted by the neoplastic hematopoietic cells and appear to promote the growth and proliferation of the leukemic cells in an autocrine fashion. More importantly, angiogenic factors play a role in the clinical behavior and outcome of both AML and MDS. Despite significant overlap between MDS and AML in many aspects, higher levels of cellular VEGF and lower levels KDR are seen in MDS than in AML. Antiangiogenic therapy may play a role in AML and MDS and some differences in response may exist between MDS and AML.
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PMID:Angiogenesis in acute myeloid leukemia and myelodysplastic syndrome. 1181 14

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

We investigate the role of mutations of receptor tyrosine kinases as well as their downstream scaffold molecules in leukemogenesis of acute myeloid leukemia (AML) in Chinese patients. Genes of interest included FLT3, PDGFRbeta, KDR, CSF2Rbeta, SOCS1, PIAS3 and SHIP. The coding sequence of these genes was analysed by the reverse transcription-polymerase chain reaction to search novel mutations. A novel mutation (A > T, Q1154L) of SHIP (1 of 192, 0.52%) was identified and another novel mutation (C > T, R685C) of PDGFRbeta (2 of 192, 1.04%). In addition, FLT3 mutations were seen in three of five patients with AML following myelodysplastic syndrome (60%) and 39 of 268 (14.6%) de novo AML patients (P < 0.05). No mutations were found in the coding sequence regions of KDR, CSF2Rbeta, SOCS1 or PIAS3.
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PMID:The investigation of mutation and single nucleotide polymorphism of receptor tyrosine kinases and downstream scaffold molecules in acute myeloid leukemia. 1716 6

This study was purposed to investigate the significance of genomic comprehensive analysis information in diagnosis, therapy and prognosis of MDS through comprehensive analysis of a patient with MDS. The bone marrow specimen from a patient with MDS was comprehensively analyzed by a combination of genomic approaches, including chromosomal karyotyping, fluorescence in situ hybridization (FISH), genome scanning using Affymetrix high density SNP microarray platform, and next-generation sequencing (NGS) analysis using IonTorrent Cancer Gene Panel. The results showed that an abnormal clone was identified by standard G-banding karyotyping and confirmed by FISH, which contains interstitial deletions on the long arms of chromosome 5 and 11 respectively. SNP-array analysis defined the two genomic deletions to be an 81 Mb interstitial deletion on the long are of chromosome 5 and a 24 Mb interstitial deletion on the long are of chromosome 11. Meanwhile, SNP-array detected two genomic regions with acquired loss of heterozygosity (LOH), a 58 Mb region on the short arm of chromosome 1 and a 39 Mb region on the distal end of the long arm of chromosome 14. In addition, SNP-array identified multiple genomic regions with long stretch of absence of heterozygosity, representing about 5.3% of autosomal genome, indication a certain level of consanguinity between the parents. No clinically significant gene mutation was identified using IonTorrent 50 Cancer Gene Panel while 6 polymorphisms within 6 genes were observed including APC, FGFR3, KDR, KIT, PDGFRA, and RET. It is concluded that the combined genomic techniques are necessary to provide a full picture of the patient's genomic alterations. Some of the acquired genomic findings are important for the diagnosis and therapy selection. Germline genomic alterations warrant genetic counseling and are useful for further studies to explore the mechanisms leading to tumorigenesis of MDS patient.
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PMID:[Comprehensive analysis of genomic detection for a patient with myelodysplastic syndrome]. 2437 37

Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.
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PMID:Detection of an activated JAK3 variant and a Xq26.3 microdeletion causing loss of PHF6 and miR-424 expression in myelodysplastic syndromes by combined targeted next generation sequencing and SNP array analysis. 2467 52

Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) not fit for intensive treatment need novel therapy options. Vascular endothelial growth factor (VEGF) receptor inhibition is one potential mechanism by which AML and MDS could be treated. The receptor tyrosine kinase inhibitor AZD2171 (cediranib) has activity against VEGF receptors KDR and FLT-1. This multicenter phase II study was designed to test cediranib's activity in patients with AML or high-risk MDS. The primary endpoint was confirmed disease response defined as a composite of complete remission, partial remission or hematologic improvement. The study enrolled 23 subjects in the AML cohort and 16 subjects in the MDS cohort. There were no confirmed responses in either group. Since the study met the stopping rule after the first stage of enrollment, the trial was closed to further accrual. Common adverse events in both cohorts included thrombocytopenia, neutropenia, anemia, fatigue, dyspnea, diarrhea, nausea and dehydration.
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PMID:A phase II study of AZD2171 (cediranib) in the treatment of patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. 2532 7

It is well known that vascular endothelial growth factors (VEGFs) and their receptors (vascular endothelial growth factor receptors, VEGFRs) are expressed in different tissues, and VEGF-VEGFR loops regulate a wide range of responses, including metabolic homeostasis, cell proliferation, migration and tubuleogenesis. As ligands, VEGFs act on three structurally related VEGFRs (VEGFR1, VEGFR2 and VEGFR3 [also termed FLT1, KDR and FLT4, respectively]) that deliver downstream signals. Haematopoietic stem cells (HSCs), megakaryocytic cell lines, cultured megakaryocytes (MKs), primary MKs and abnormal MKs express and secrete VEGFs. During the development from HSCs to MKs, VEGFR1, VEGFR2 and VEGFR3 are expressed at different developmental stages, respectively, and re-expressed, e.g., VEGFR2, and play different roles in commitment, differentiation, proliferation, survival and polyplodization of HSCs/MKs via autocrine, paracrine and/or even intracrine loops. Moreover, VEGFs and their receptors are abnormally expressed in MK-related diseases, including myeloproliferative neoplasms, myelodysplastic syndromes and acute megakaryocytic leukaemia (a rare subtype of acute myeloid leukaemia), and they lead to the disordered proliferation/differentiation of bone marrow cells and angiogenesis, indicating that they are closely related to these diseases. Thus, targeting VEGF-VEGFR loops may be of potential therapeutic value.
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PMID:Effects of vascular endothelial growth factors and their receptors on megakaryocytes and platelets and related diseases. 2907 33

Vascular endothelial growth factor C (VEGFC) stimulates leukemia cell proliferation and survival, and promotes angiogenesis. We studied VEGFC expression in bone marrow samples from 353 adult acute myeloid leukemia (AML) patients and its relationship with several clinical, cytogenetic, and molecular variables. We also studied the expression of 84 genes involved in VEGF signaling in 24 patients. We found that VEGFC expression was higher in AML patients with myelodysplasia-related changes (AML-MRC) than in patients with non-AML-MRC. We also found an association between VEGFC expression and the patient cytogenetic risk group, with those with a worse prognosis having higher VEGFC expression levels. No correlation was observed between VEGFC expression and survival or complete remission. VEGFC expression strongly correlated with expression of the VEGF receptors FLT1, KDR, and NRP1. Thus, in this series, VEGFC expression was increased in AML-MRC and in subgroups with a poorer prognosis, but has no impact on survival.
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PMID:Bone marrow VEGFC expression is associated with multilineage dysplasia and several prognostic markers in adult acute myeloid leukemia, but not with survival. 2934 76