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)

The MLL gene at 11q23 is frequently disrupted by chromosomal translocations in de novo acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), and in secondary leukemia induced by treatment with inhibitors of topoisomerase II, including the epipodophylotoxins. The CBFA2 gene at 21q22 is also frequently disrupted in de novo ALL and AML and less commonly in secondary AML. Rearrangements of MLL and CBFA2 have been described in de novo and secondary myelodysplastic syndrome (MDS). There have been no previous descriptions of coexisting abnormalities of MLL and CBFA2 in cases of MDS or acute leukemia. We describe a patient who developed secondary MDS after chemotherapy for hyperdiploid ALL. At the time of conversion to MDS, the patient had 46 chromosomes, with an 11q23/MLL translocation involving a new partner breakpoint at 2p23 and a 21q22/CBFA2 translocation involving a new partner breakpoint at 6p22. This report is the first to describe new partner breakpoints at 2p23 and 6p22 for MLL and CBFA2 genes, respectively, and concurrent rearrangements of these genes in a patient with secondary MDS.
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PMID:Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia. 1082 8

We report a 50-year-old man who developed therapy-related myelodysplastic syndrome after treatment with etoposide-including chemotherapy for extratesticular germ cell tumor. Chromosomal analysis showed inversion 11 (p15q22) translocation. Reverse transcriptase-polymerase chain reaction amplification of patient RNA showed a fusion transcript of nucleoporin gene NUP98, and putative DEAD-box RNA helicase gene DDX10. NUP98 is implicated in the transformation through aberrant nucleocytoplasmic transport. DDX10 is suggested to be involved in ribosome assembly. The NUP98-DDX10 fusion transcript may promote the development of secondary hematological malignancies caused by DNA-topoisomerase II inhibitors through aberrant nucleocytoplasmic transport and/or alteration in ribosome assembly.
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PMID:Fusion of the nucleoporin gene, NUP98, and the putative RNA helicase gene, DDX10, by inversion 11 (p15q22) chromosome translocation in a patient with etoposide-related myelodysplastic syndrome. 2575 91

Chromosomal aberrations are frequently associated with therapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) and are thought to result from exposure to genotoxic drugs, including alkylating agents and DNA topoisomerase II poisons. The NUP98 gene on chromosome band 11p15 is involved in several different chromosomal aberrations that have been associated with t-MDS/AML. We have cloned the translocation breakpoints from two cases of t-MDS harboring a t(11;20)(p15;q11). Sequence analysis of the breakpoints from both cases revealed almost perfectly balanced translocations between NUP98 and TOP1. There were no known recombinogenic sequences identified at or near the breakpoints. However, four bp microduplications present at the translocation crossover points suggested that these translocations may have been initiated by 4 bp staggered double-stranded DNA breaks, which are known to be associated with the action of topoisomerase II. Given the history of patient exposure to topoisomerase II poisons, and the fact that these drugs stabilize staggered breaks with a 4 bp overhang, it seems possible that drug-induced topoisomerase II cleavage and subunit exchange was involved in these translocations. These results suggest that NUP98 is a recurrent target for therapy-related malignancies induced by multiagent chemotherapy, and suggest a role for DNA topoisomerase II poisons in the generation of these translocations. Published 2000 Wiley-Liss, Inc.
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PMID:Potential role for DNA topoisomerase II poisons in the generation of t(11;20)(p15;q11) translocations. 1095 88

The incidence of secondary myelodysplastic syndromes and acute leukemia (MDS/AL) was reported for 395 patients autografted for Hodgkin's disease (HD) (n = 96) and non-Hodgkin's lymphoma (NHL) (n = 299) between 1987 and 1998. Eleven patients developed secondary MDS/AL (crude rate at 2.8%) including two lymphoblastic AL cases. The mean time of occurrence was at 32 months after autologous stem cell transplantation (ASCT) and 71 months after diagnosis. The estimated actuarial incidence at 10 years was at 6.3% (+/-4%). Karyotyping revealed complex chromosomal aberrations in only one patient, and two translocations [t(8;21) and t(8;16)]. No features of topoisomerase II inhibitor-related leukemia were found. Only one patient had received ASCT in first remission. The remaining 10 patients had received multiple courses of chemotherapy before stem cell collection and four had relapsed after ASCT and before the occurrence of secondary MDS/AL. Five of 11 patients had received localized radiotherapy and five others received TBI in their conditioning regimen. Ten patients died despite chemotherapy and/or supportive care and only one patient is alive and well after genoidentical allogeneic transplantation. We suggest a cumulative leukemogenic role of pre-ASCT radiation and chemotherapy in the occurrence of these secondary MDS/AL more than the high-dose therapy itself.
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PMID:Myelodysplasias and leukemias after autologous stem cell transplantation for lymphoid malignancies. 1096 73

Standard antileukemic chemotherapy induces complete remission in approximately half of patients with high-risk (HR) myelodysplastic syndrome (MDS). Intensification of induction therapy by the use of intermediate- or high-dose cytosine arabinoside in combination with fludarabine, idarubicin, or topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg, topoisomerase inhibitors (topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of chemotherapy, remissions are short, even with continuation of intensive postremission therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype refractory anemia with excess blasts in transformation. Further intensification of either induction chemotherapy or postremission therapy is unlikely to improve results with current drug combinations. With these results at hand, the role of intensive chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic bone marrow transplantation (BMT). Regimens with low early mortality, eg, topotecan plus intermediate dose Ara-C, could also be used to reduce tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-tumor reaction. New agents, such as farnesyl transferase inhibitors (ras inhibitors), drug-antibody conjugates (Myelotarg), thalidomide, arsenic trioxide, maintenance chemotherapy with hypomethylating agents, or oral topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.
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PMID:Intensive chemotherapy for patients with high-risk myelodysplastic syndrome. 1103 61

Chemotherapy of secondary leukemias is currently still considered to be associated with poor results. However, recent data suggest that the response to remission induction may substantially differ according to the previous medical history of the patients. Therapy related leukemia, arising following exposure to previous alkylating agents or radiotherapy, is often associated with chromosomal abnormalities involving chromosomes 5 and 7 and has a particularly bad response, whereas AML after exposure to epipodophyllotoxins or topoisomerase-II active agents could have a somewhat better response. Acute promyelocytic leukemia secondary to treatment of a primary malignant neoplasm seems to be associated with a better response if compared to other cytotypes of AML or to AML arising after transformation of myelodysplasia. However, here the literature data are not in full agreement, as different kinds of approaches have been applied. In fact, even if the problems encountered in treating patients with secondary leukemia are similar to those seen in patients with AML arising in a background of myelodysplasia (resistant disease and prolonged cytopenia after treatment), there are data suggesting that the use of high dose ara-C, with or without fludarabine, can circumvent resistance in a small but significant number of cases. One of the unsolved problems which still remains is how to consolidate the CR induced with high dose ara-C or with cycles based on anthracycline derivatives. In addition, another question relates to the categories of patients in whom chemotherapy may change the expected survival. Intensive post-remission chemotherapy, with or without autologous HSCT, may constitute an appropriate alternative for patients lacking a suitable sibling donor or for older patients who are in remission after chemotherapy and also able to tolerate other cycles of intensive chemotherapy. In this respect, the specific cytogenetic abnormality involved should be considered the most important prognostic factor for response and disease free survival; patients with abnormalities of chromosome 5 and 7 have a particularly low possibility of response and duration of CR. Furthermore, it is still debatable whether patients, especially the elderly, with these characteristics should go through a series of conventional treatments or just receive supportive treatment. On the other hand, patients with better prognostic factors should be entitled to further intensive treatments, taking into account possible delayed recovery and/or possible less successful collection of peripheral or marrow stem cells.
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PMID:Chemotherapy of secondary leukemias. 1104 14

The use of all trans-retinoic acid and combination chemotherapy has made acute promyelocytic leukemia (APL) a potentially curable leukemia. Late sequelae of the treatment of APL have therefore become an important consideration in the overall treatment strategy. We report a patient with APL who achieved complete clinical and molecular remission after treatment with the topoisomerase II inhibitors daunorubicin, mitoxantrone, etoposide, and the anti-metabolite cytosine arabinoside. Seven years later, she developed therapy-related myelodysplastic syndrome (t-MDS) without any evidence of relapse of the APL clone. Karyotypic and molecular cytogenetic analysis showed complex cytogenetic aberrations, including deletion of the long arm of chromosome 5, monosomy 7, but without rearrangement of the MLL gene/11q23. Interestingly, this case would be classified clinically as "epipodophyllotoxin related MDS," but pathologically as "alkylating-agent related MDS" according to the recently proposed World Health Organization (WHO) classification system for MDS. This case of t-MDS in an APL patient in durable remission highlights the importance of avoiding long-term treatment related toxicities, as APL is a potentially curable leukemia.
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PMID:Therapy-related myelodysplastic syndrome after eradication of acute promyelocytic leukemia: cytogenetic and molecular features. 1117 6

Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic illudin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Irofulven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS). Irofulven was given as an intravenous infusion over five minutes daily for five days. The starting dose was 10 mg/m2/day (50 mg/m2/course). Courses were scheduled to be given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty patients [AML: 17 patients; MDS: one patient; ALL: one patient; mixed lineage acute leukemia: one patient] were treated. Nausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulmonary edema were dose limiting toxicities, occurring in two of five patients treated at 20 mg/m2/day and two of three patients treated at 12.5 mg/m2/day. The MTD was defined as 10 mg/m2/day for five days. One patient with primary resistant AML achieved complete remission. Proposed phase II studies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single agent and in combination regimens, particularly with topoisomerase 1 inhibitors.
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PMID:Phase I study of irofulven (MGI 114), an acylfulvene illudin analog, in patients with acute leukemia. 1129 29

The translocation t(11;16)(q23;p13) has only been documented in patients with acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We have established a myeloid cell line (SN-1) with the MLL-CBP fusion gene from an acute leukemia patient with t(11;16)(q23;p13). Although SN-1 cells were not induced to differentiate by all-trans retinoic acid (ATRA) and 1alpha,25-dihydroxyvitamin D(3) (VD3), retinoid X receptor (RXR) agonists, such as 9-cis retinoic acid and Ro48-2250, effectively induced differentiation of the cells. Downregulation of the expression of the MLL-CBP fusion gene occurred during the differentiation of SN-1 cells. When SN-1 cells were treated with MLL-CBP antisense oligonucleotide, the cells were induced to differentiate by ATRA or VD3, suggesting that the MLL-CBP fusion gene dominant-negatively suppresses ATRA- or VD3-induced differentiation. Moreover, suboptimal concentrations of sodium butyrate, a histone deacetylase inhibitor, had a cooperative effect with ATRA or VD3 in inducing the differentiation of SN-1 cells. The downregulation of the expression of MLL-CBP mRNA was accompanied by the induction of differentiation. These findings suggest that RXR agonists or a clinically applicable combination of ATRA and butyrate derivatives might be useful for differentiation therapy in leukemia patients with the MLL-CBP fusion gene.
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PMID:Downregulation of MLL-CBP fusion gene expression is associated with differentiation of SN-1 cells with t(11;16)(q23;p13). 1131 67

Secondary leukaemias are common, accounting for more than 40% of all patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). A clinical history of exposure to haematotoxins or radiation is helpful; however, many older patients are diagnosed with leukaemia with no antecedent history of exposure. These patients' disease show a remarkably similar phenotype to classic therapy-related leukaemia. The specific cytogenetic abnormalities common to MDS, alkylating-agent-related AML and poor-prognosis AML (3q-, -5, 5q-, -7, 7q-, +8, +9, 11q-, 12p-, -18, -19,20q-, +21, t(1;7), t(2;11)), probably reflect a common pathogenesis distinct from that of other de novo AMLs, although the pathogenetic pathway has yet to be elucidated. Possibly, tumour suppressor genes are implicated and genomic instability may be a cause of multiple unbalanced chromosomal translocations or deletions. Typically, these patients are either elderly or have a history of exposure to alkylating agents or environmental exposure 5-7 years prior to diagnosis. Another distinct entity affects the mixed lineage leukaemia (MLL) gene located on 11q23. These account for about 3% of patients with therapy-related leukaemia and have a short latency period from exposure, usually to an inhibitor of topoisomerase II. Other therapy-related patients with t(8:21), inv16 or t(15;17) translocations should be treated as any other de novo AML with similar cytogenetics. In summary, the major prognostic factor is related to the pathogenetic mechanisms of the leukaemia. Cytogenetics and molecular features are a better predictor of outcome than patient history. Patients should receive standard induction therapy. However, the long-term outcome is relatively poor; the best results being obtained among patients undergoing allogeneic transplantation.
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PMID:Biology and therapy of secondary leukaemias. 1135 27


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