UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nuclear transcription factor NF-kappa B regulates cell survival, proliferation, and differentiation. Little is known about NF-kappa B in myeloid malignancies. In this report, we assessed NF-kappa B in a group of myeloid neoplasms by using an electrophoretic mobility shift assay (EMSA) and immunofluorescence methods in freshly isolated leukemia cells. We analyzed 30 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 3 cases of chronic myelomonocytic leukemia (CMML), 15 cases of chronic myeloid leukemia in chronic phase (CML-CP), and 2 cases of chronic myeloid leukemia in blast crisis (CML-BC). Unstimulated cells (bone marrow and peripheral blood) from 17 normal donors and apheresis samples from 6 peripheral blood stem cell donors treated with granulocyte colony-stimulating factor (G-CSF) were used as controls. When EMSA was used, NF-kappa B was elevated in 14 of 30 (47%) cases of AML, in both cases of CML-BC, and in all reference donors treated with G-CSF, but it was at basal levels in all cases of MDS and CML-CP and in normal donors (P = <.01). Immunofluorescence analysis confirmed strong nuclear RelA/NF-kappa B immunoreactivity in AML blasts but not in normal bone marrow. Bcl-2, a downstream molecule, was expressed in cases with elevated NF-kappa B, but not in cases with basal levels of NF-kappa B, suggesting that NF-kappa B is active and provides the cells with survival advantages in vivo. These results suggest that suppression of NF-kappa B may be a useful therapeutic strategy for a subset of patients with AML.
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PMID:Expression of constitutively active nuclear-kappa B RelA transcription factor in blasts of acute myeloid leukemia. 1499 44

Chromosomal rearrangements involving 3q26 either due to inversion or translocation with various partner chromosomes are a recurrent finding in malignant myeloid disorders. Typically, these chromosome aberrations contribute to ectopic expression of or to the formation of fusion genes involving the EVI1 proto-oncogene. Chromosomal translocations involving the short arm of chromosome 2 (p15-p23) and the distal part of the long arm of chromosome 3 (q26-q27) are a rare but recurrent finding in patients with myeloid malignancies, and are assumed to be part of this spectrum of disorders. Thus far, however, these translocations have been poorly studied. Here, we present 21 new cases with myelodysplasia, acute myeloid leukemia or CML in blast crisis, which upon karyotyping showed the presence of a t(2;3). Furthermore, an extensive literature review disclosed 29 additional cases. Morphological, clinical and cytogenetic assessment revealed the typical hallmarks of 3q26/EVI1 rearrangements, that is, trilineage dysplasia and dysmegakaryopoiesis, poor prognosis and additional monosomy 7. Molecular cytogenetic analysis and PCR in selected samples indicated that in most cases the translocation indeed targets the EVI1 locus. Mapping of the chromosome 2 breakpoints confirmed the initially suspected cytogenetic breakpoint heterogeneity at the 2p arm.
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PMID:Translocation t(2;3)(p15-23;q26-27) in myeloid malignancies: report of 21 new cases, clinical, cytogenetic and molecular genetic features. 1508 64

Clofarabine [Clofarex] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute. In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine. Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute. Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003. In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio. Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license. Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing. The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML). In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL. A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported. In May 2004, Bioenvision announced that it had decided to stop enrollment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enroll approximately 65 patients with AML considered unsuitable for intensive chemotherapy. Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe. In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2-6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia. In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment. As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002. Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers. A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.
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PMID:Clofarabine. 1523 Jun 27

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.
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PMID:Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia. 1528 43

CREB-binding protein (CBP) and highly related p300 protein are transcriptional co-activators that play an essential role in chromatin remodeling through histone acetyltransferase activity and interaction with other transcriptional regulators. In this study, various hematological malignancies, including nine cell lines and 45 clinical samples (32 acute myeloid leukemias (AML), nine acute lymphoblastic leukemias (ALL), two cases of myelodysplastic syndrome (MDS), one multiple myeloma, and one chronic myelogenous leukemia in blast crisis), were examined to ask whether mutation of the CBP and p300 genes could be involved in leukemogenesis. The answer was approached by employing the reverse transcription-polymerase chain reaction and single-strand conformation polymorphism (RT-PCR/SSCP) technique and subsequent sequence analysis. A T-lymphoblastic cell line, CEM had an in-frame 21-base-pair deletion within the bromodomain of its p300 cDNA. Genomic DNA analysis revealed aberrant splicing caused by mutation of the acceptor site of intron 17 from ag to gg, which should interfere with catalytic step II of the pre-mRNA splicing reaction. In 1 MDS patient, a missense mutation was detected, which caused a replacement from Ser to Gly at codon 507 of p300. This is the first report of CBP/p300 mutations in leukemias, which might be relatively rare but nonetheless contribute to pathogenesis in some fraction of cases.
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PMID:Disease-related potential of mutations in transcriptional cofactors CREB-binding protein and p300 in leukemias. 1531 79

The leukemic fusion gene AML1-MDS1-EVI1 (AME) encodes a chimeric transcription factor that results from the t(3,21)(q26;q22) translocation seen in patients with acute myeloid leukemia, with therapy-related myelodysplastic syndrome, or with chronic myeloid leukemia in blast crisis. The myeloid transcription factor CEBPA is crucial for normal granulopoiesis. Here, we found that conditional expression of AME suppresses CEBPA protein by 90.8% and DNA-binding activity by 93.9%. In contrast, CEBPA mRNA levels remained unchanged. In addition, we detected no differences in CEBPA mRNA levels in leukemic blasts of patients carrying the AME translocation (n = 8) compared to acute myeloid leukemia patients with a normal karyotype (n = 9). CEBPA protein and binding activity, however, were reduced significantly (100% and 92.1%, respectively) in AME patient samples. Furthermore, we observed that calreticulin (CRT), a putative inhibitor of CEBPA translation, was strongly activated after induction of AME in the cell-line system (14.8-fold) and in AME patient samples (12.2-fold). Moreover, inhibition of CRT by small interfering RNA powerfully restored CEBPA levels. These results identify CEBPA as a key target of the leukemic fusion protein AME and suggest that modulation of CEBPA by CRT may represent a mechanism involved in the differentiation block in AME leukemias.
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PMID:The leukemic fusion gene AML1-MDS1-EVI1 suppresses CEBPA in acute myeloid leukemia by activation of Calreticulin. 1532 10

The BCR/ABL tyrosine kinase inhibitor imatinib has shown remarkable efficacy in treating patients with chronic myelogenous leukemia (CML). In a small portion of patients treated with imatinib, however, the disease may progress to advanced stages, frequently accompanied by cytogenetic clonal evolution with the appearance of additional chromosomal aberrations besides the Philadelphia chromosome. Here we report the appearance of an inv(11)(p15q22) as a clonal evolution in a CML patient undergoing treatment with imatinib. Leukemic cells from the patient were found to express the fusion transcript of NUP98 and DDX10, which is in accordance with previously reported cases of de novo or therapy-related acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(p15q22). Although the patient showed resistance to imatinib with the disease rapidly progressing to blast crisis, sequence analysis failed to reveal any mutation in the kinase domain of BCR/ABL that would explain the imatinib resistance. Furthermore, ex vivo treatment of leukemic cells with imatinib significantly reduced tyrosine phosphorylation of CrkL, a target of the BCR/ABL kinase. These observations raise a possibility that the NUP98/DDX10 fusion might be involved in imatinib resistance as well as in acute transformation of CML.
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PMID:Clonal evolution with inv(11)(p15q22) and NUP98/DDX10 fusion gene in imatinib-resistant chronic myelogenous leukemia. 1572 30

Genomic aberrations of Fms-like tyrosine kinase 3 (FLT3), including internal tandem duplication (ITD) and point mutations, have been demonstrated in 25-30% of adults acute myeloid leukemia (AML) and are markers of poor prognosis. FLT3/ITD and D835 mutations were analyzed in 194 Chinese patients with acute leukemia and myelodysplastic syndromes (MDS) by polymerase chain reaction (PCR). FLT3/ITDs and D835 mutations were found in 25.9 and 6.3% of 143 AML patients, respectively. Two patients showed both ITD and point mutations. Among the FAB subtypes of AML, the rate of FLT3 aberration was significantly higher in M3 and M5. However, neither aberrations was found in 25 patients with acute lymphoblastic leukemia (ALL), 2 acute hybrid leukemia, 17 MDS and 7 chronic myeloid leukemia in blast crisis (CML-BC). FLT3/ITD was associated to leukocytosis and lower complete remission (CR) rate, and was more prevalent in patients with normal karyotype. In contrast, D835 mutation was not associated with leukocytosis or low CR rate. Our results confirm that FLT3 activating mutations also occur in a significant percentage in Chinese AML patients. FLT3/ITD(+) patients treated with standard induction regimen could achieve lower complete remission rates compared with patients not harboring this defect. Early detection of FLT3 mutations and an intensification of induction therapy might thus be useful for this group of patients to overcome the poor prognosis.
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PMID:Analysis of FLT3 internal tandem duplication and D835 mutations in Chinese acute leukemia patients. 1599 32

Cytogenetic syndrome involving bands 3q21 and 3q26, known as "3q21q26 syndrome" has been observed in adult patients with acute myelogenous leukemia (0.5-2%), chronic myelogenous leukemia in blast crisis (20%), myelodysplastic syndromes and myeloproliferative disorders. In the present study bone marrow samples from two boys (12 and 16 years), diagnosed with CML and AML respectively, were investigated using conventional cytogenetic methods, interphase "multipoint" fluorescence in situ hybridization (FISH), dual color-FISH and multiplex FISH. The "multipoint" FISH analysis identified in de novo childhood AML case an inv(3)(q21q26) and a complex 3q rearrangement including inversion and duplication in the CML case. The "3q21q26 syndrome" is associated with normal or elevated platelet counts with marked abnormalities of megakaryocytopoiesis, involvement of multiple hematopoietic lineages. The affected patients were resistant to conventional chemotherapy and had a short survival. This syndrome is very rare in de novo childhood AML, and simultaneous presence of 3q inversion and duplication, to our knowledge, has not yet been identified in hematological malignancies. The results of our study emphasize the importance of classical and modern cytogenetic analysis in the diagnosis of hematologic malignancies, because in the majority of cases they can provide additional diagnostic information for the clinicians in deciding the best therapeutic approach, precise classification and prognosis of the disease.
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PMID:[Identification of 3q21q26 syndrome by "multipoint" interphase FISH analyses in childhood myeloid leukemia]. 1624 10

The WHO classification published in 2001 defined a new category of hematological disease, myelodysplastic/myeloproliferative diseases (MDS/MPD), that have both myelodysplasia and myeloproliferation at the time of initial presentation. This category consists of four subclasses, chronic myelomonocytic leukemia (CMML), atypical CML(aCML), juvenile chronic myelogenous leukemia and MDS/MPD-unclassifiable (MDS/MPD-u). In order to clarify the clinical features of these diseases, we analyzed clinical data of tentatively diagnosed MDS/MPD cases in the past ten years accumulated from affiliated hospitals. By reviewing the data of each case according to the criteria, we diagnosed 31 cases of MDS/MPD, including 22 cases of CMML, 5 cases of aCML and 4 cases of MDS/MPD-u. Male predominance and high age were common among these three subclasses. The prognosis of CMML was poor compared to other subclasses because of the high incidence of blast crisis. It is noteworthy that blast crisis in CMML exclusively occurred within one year after diagnosis. Young age, a high percentage of blasts in the peripheral blood, splenomegaly, lymphadenopathy and clonal cytogenetic abnormality were associated with blast crisis. It is suggested that there are two subgroups in CMML which differ in disease progression. Thus, these indicators may be useful in deciding the therapeutic strategy including hematopoietic cell transplantation for the high risk subgroup. There were four MDS/MPD cases with a history of preceding hematological diseases, such as aplastic anemia, MDS or malignant lymphoma. Among these, three cases with a long-term history of treatment with metenolone acetate developed CMML. It is suggested that the long-term effect of androgen plays a role in the pathophysiology of CMML.
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PMID:[Clinical features of a new category, myelodysplastic/myeloproliferative diseases, defined by WHO classification]. 1663 72

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