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 frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.
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PMID:[Leukemias induced by anticancer chemotherapies]. 1058 9

We describe a 73-year-old man diagnosed with acute myelomonocytic leukemia (AML-M4) following myelodysplasia with trisomy 11 and with a t(11;11;22). This is the first case with both abnormalities present in the same cells and with the t(11;11;22) involving a chromosome 11 already duplicated at 11q23. This band contains the MLL gene that undergoes partial tandem duplication in patients with +11, which is "promiscuous," being translocated with a large number of genetic partners. Our patient had a complex karyotype that was completely defined by in situ hybridization. This technique demonstrated that the t(11;11;22) derivative with a duplication of band 11q23 carried from three to four copies of MLL. Two copies of the gene were close to each other and centromeric to the break-point region. Therefore, a partial tandem duplication of the MLL gene might have happened before the occurrence of t(11;11;22). Considering the associated chromosome defects, the monosomy for the long arm of chromosome 7, due to an unbalanced translocation t(7;17), further underlines the possibility that a partial tandem duplication of the MLL gene might have taken place.
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PMID:Trisomy 11 and a complex t(11;11;22) in a patient with acute myelomonocytic leukemia (AML-M4) following myelodysplasia (MDS): a cytogenetic study of a mechanism of leukemogenesis. 1064 Jan 42

Gene amplification is one of the mechanisms for activating proto-oncogenes resulting in an enhanced expression of the corresponding gene product. By fluorescence in situ hybridization (FISH), amplification of the proto-oncogene MLL has been described only in seven patients with acute myeloid leukemia (AML). We report five new patients (four had de novo AML, one had a de novo myelodysplastic syndrome) displaying different mechanisms of MLL amplification, suspected by G-banding and confirmed by FISH analysis. In two patients, MLL was amplified on double-minute chromosomes (dmins). In both cases, an interstitial deletion in 11q23 including the MLL gene was associated with the occurrence of the dmins containing MLL. As a rarely described mechanism, MLL amplification in the form of size-variable ring chromosomes was observed in two patients. Remodeling of the ring chromosomes leads to multiple copies of MLL and obviously provided a selective growth advantage. In one of the two cases with ring chromosomes, the centromeric alpha-satellite DNA of the ring chromosome was not detectable. Our fifth patient showed the unique finding of MLL amplification within a uniformly (homogeneously?) stained region in interaction with amplified ribosomal DNA sequences. Also, one of the patients with ring chromosomes exhibited the amplification of ribosomal DNA on the ring chromosomes. The transcriptionally active genes for ribosomal RNA could probably enhance the expression of MLL. In one of our five patients, we found the new combination of concomitant amplification of the proto-oncogenes MLL and MYC.
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PMID:Amplification of the MLL gene on double minutes, a homogeneously staining region, and ring chromosomes in five patients with acute myeloid leukemia or myelodysplastic syndrome. 1071 68

Acute myeloid leukemia with minimal signs of myeloid differentiation (AML-M0) is a recent addition to the FAB group classification. Chromosome data is scarce, but existing reports describe a high incidence of complex karyotypes and myelodysplastic syndrome-like chromosome alterations, while single chromosome translocations have rarely been reported. We describe the case of a 60-year-old woman diagnosed with AML-M0 with a novel translocation t(11;12)(q23-24;q24) as the sole karyotypic marker. Fluorescence in situ hybridization analysis to assess MLL gene splitting did not show rearrangement of this oncogene.
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PMID:A novel t(11;12)(q23-24;q24) in a case of minimally-differentiated acute myeloid leukemia (AML-M0). 1073 97

It is known that alkylating agents and topoisomerase II inhibitors can cause distinct forms of therapy-related leukemia and myelodysplastic syndrome (TRL/MDS). Although several reports have been made on each of these agents separately, no study has yet been conducted to evaluate the effect of these two types of agents in the same population. In a nationwide, large-scale population study, the clinical and cytogenetic features as well as the prognostic factors in 256 patients with TRL/MDS were assessed. Median age was 61 years, and the median period of latency from primary malignancies was 47.9 months. The latency period was significantly shorter in patients undergoing chemotherapy, especially that of topoisomerase II inhibitors, for primary cancer. The morphological diagnosis of TRL/MDS was acute myeloid leukemia in 59% and MDS in 41% of patients. Chromosome abnormalities that frequently involved chromosomes 5, 7 or 11 were documented in 77% of the 189 patients examined. MLL gene rearrangements were detected in 11 of 58 subjects and were correlated with a borderline significance (P = 0.072) with topoisomerase II inhibitor administration. Overall median survival was only 9.7 months. Survival was similar in cases with or without MLL gene rearrangement. Multivariate analysis identified chromosome 5 abnormalities, hypoproteinemia, poor therapy outcomes for primary cancer, C-reactive protein, and thrombocytopenia as being significantly poor prognostic factors (P < 0.05). This large-population study provided a comprehensive update of TRL/MDS status in Japan, identified significant prognostic factors, and enabled the clinical significance of MLL gene rearrangement to be assessed.
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PMID:Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors. 1074 24

Gene CBP codes for a transcriptional coactivator, which can interact with many transcriptional factors. It modifies the process of transcription stimulated by these factors by specific binding to RNA polymerase II holoenzyme or by histone acetylation. CBP gene mutation is the molecular cause of autosomal dominant genetic disease called Rubinstein-Taybi syndrome that is manifested by mental and growth retardations, by typical face malformations and broad thumbs and broad big toes. The CBP gene can be affected by the t(8;16)(p11;p13.3) translocation resulting in production of the MOZ/CBP chimeric protein and in induction of acute myeloblastic leukaemia. Therapy using topoisomerase II inhibitors can induce the t(11;16)(q23;13.3) translocation causing acute myeloid or lymphoid leukaemia or myelodysplasia through production of the MLL/CBP protein chimera.
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PMID:[Clinical sequelae of mutation of the CBP gene]. 1074 38

Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencing of the RT-PCR products of all 16 positive cases revealed fusions of MLL exon 9/exon 3 (e9/e3) (six cases), e10/e3 (three cases), e11/e3 (four cases) or combinations of differentially spliced e10/e3 and e11/e3 (three cases) transcripts. The duplications were confirmed by genomic long range PCR and Southern blot hybridization. Twelve cases with the MLL duplication were de novo myeloid leukemia, one was a secondary AML after MDS, three were therapy-related AML (t-AML). Of the 16 MLL-duplication positive cases, seven were classified as FAB M2, two as M1, five as M4, one as M0, one as M5b. The mean age was 62.3 years for patients with MLL duplication vs 50.3 years for the control group. Of 15 adult patients, 12 received treatment. Of these, three were nonresponders, five had early relapse (< or =6 months), four relapsed between 7 and 12 months. Median survival and relapse-free interval of the MLL duplication positive group was significantly worse than those of an age-matched karyotypically normal control group. In conclusion, MLL tandem duplications (1) are less common than previously reported; (2) are preferentially observed in AML with normal karyotypes, but can also be found in the presence of chromosome alterations; (3) are not strongly associated with an FAB subtype; (4) were not observed with the prognostically favorable t(8;21), inv(16), and t(15;17), other recurrent translocations, or in complex karyotypes; and (5) identifies a subgroup of patients with an unfavorable prognosis.
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PMID:Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. 1080 9

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

As a result of the recurring translocation t(11;16) (q23;p13.3), MLL (mixed-lineage leukemia) is fused in frame to CBP (CREB binding protein). This translocation has been documented almost exclusively in cases of acute leukemia or myelodysplasia secondary to therapy with drugs that target DNA topo isomerase II. The minimal chimeric protein that is produced fuses MLL to the bromodomain, histone acetyltransferase (HAT) domain, EIA-binding domain and steroid-receptor coactivator binding domains of CBP. We show that transplantation of bone marrow retrovirally transduced with MLL-CBP induces myeloid leukemias in mice that are preceded by a long preleukemic phase similar to the myelodysplastic syndrome (MDS) seen in many t(11;16) patients but unusual for other MLL translocations. Structure-function analysis demonstrated that fusion of both the bromodomain and HAT domain of CBP to the amino portion of MLL is required for full in vitro transformation and is sufficient to induce the leukemic phenotype in vivo. This suggests that the leukemic effect of MLL-CBP results from the fusion of the chromatin association and modifying activities of CBP with the DNA binding activities of MLL.
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PMID:Chromatin-related properties of CBP fused to MLL generate a myelodysplastic-like syndrome that evolves into myeloid leukemia. 1097 Aug 58

Several studies have demonstrated the prognostic value of cytogenetic analysis in MDS both for survival and progression to AML. However it is unknown which are the numerical or structural abnormalities required for leukemic transformation. In this report we studied clinically and cytogenetically 127 patients: 125 with primary MDS and two with AML with a previous history of MDS. Thirty-one patients (24%) showed evolution of the disease during the follow-up study. Chromosomal abnormalities found at diagnosis in patients that progressed toward AML included: del(5)(q15), +6, del(6)(q21), t(5;8)(q32;q22),-7, del(7)(q22), der(7)t(1;7)(q10;p10), t(7;11)(p15;p15), +8, del(11)(q23), del(12p), del(3)(q21), del(20)(q12) and complex karyotypes. Eight of these patients were studied cytogenetically during transformation and showed acquisition of chromosomal alterations involving dup(1q), +8, del(11)(q23), and translocations between chromosomes 1 and 8 or 7 and 17. In addition we also observed gain of ploidy and monosomy 21. These results suggest that chromosomal alterations during evolution of the disease include special chromosome gains or abnormalities of chromosomes 1, 7, 8, 11 and 17 with involvement of ETV-1, Hox-A9, Pax 4, MLL genes besides a putative gene mapped at 17q25. We also applied the International Prognostic Scoring System (IPSS) to 114 patients, excluding those submitted to allogeneic bone marrow transplant. Our patients were classified into four distinct risk groups. The analysis of risk groups presented by 27 patients who showed evolution of the disease revealed 18 at the high risk group and four at the intermediate-2 group. From the intermediate-1 risk group only five patients showed evolution of the disease. Three of these patients evolved from RA to RAEB with gain of a del(11)(q23) or an expansion of a del(12)(p12) clone. Our results suggest that some chromosomal alterations are responsible for each step in the evolution of the disease. As the pathway of evolution is not unique it has been very difficult to define what genetic alteration comes first. However from several results in the literature and our own, it seems that some chromosomal alterations may predict the evolution of the disease and are correlated with short survival, as for example the trisomy of chromosome 8, and might be incorporated in the high risk group in the IPSS. This score system has been proved to be useful for predicting survival and evolution from MDS to AML.
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PMID:Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. 1099 2

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