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

The myelodysplastic syndromes (MDS) are a group of hematologic disorders commonly affecting elderly persons and often leading to acute myelogenous leukemia (AML). Although rare in children, when MDS does occur, it is frequently part of a congenital disorder such as Shwachman-Diamond syndrome (SDS). Monosomy 7 and/or deletion of part or all of 7q are poor prognostic signs in MDS and AML, although the pathophysiologic relationship between this finding and MDS or AML is unclear. Shwachman-Diamond syndrome is an inherited illness characterized by exocrine pancreatic insufficiency and by congenital neutropenia. Patients with SDS are at increased risk of developing myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Because monosomy 7 is a poor prognostic sign in MDS and AML, establishing its presence is important. However, different methods of detection of monosomy 7 may lead to different results in some patients. We present the case of a 10-year-old girl known to have SDS, who had a bone marrow aspiration and biopsy done to rule out MDS and AML. By light microscopy, the patient's bone marrow was unremarkable. GTG-banding showed the following karyotype: 45,XX,-C[3]/47,XX,+C[1]/46,XX[45]. Fluorescence in situ hybridization (FISH) was performed with a chromosome 7-specific alpha-satellite probe (D7Z1). Almost all (373 of 376) cells exhibited only one chromosome 7 signal. A second marrow aspiration done 6 months later showed an essentially normal karyotype by GTG-banding. Fluorescence in situ hybridization with the same chromosome 7 probe showed 230 of 250 cells to be monosomic for chromosome 7. A whole chromosome 7 painting probe demonstrated disomy for chromosome 7 in 90 of 90 cells; however, subtle heteromorphism in the centromeric regions of the 2 copies of chromosome 7 was noted in some cells. This case demonstrates that FISH and GTG-banding can give discordant results, that the two should be viewed as complementary technologies, and that both have a place in a full karyotypic analysis. Furthermore, this case demonstrates for the first time that heteromorphism and/or subtle structural abnormalities of chromosome 7, previously associated with MDS and AML, can exist without clinical or morphologic signs of these illnesses. It will be of interest to further study the relationship, if any, between SDS and various structural abnormalities of chromosome 7 in MDS and AML, and to elucidate the molecular mechanisms of pathogenesis, physiology, and treatment of these disorders.
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PMID:Discordant detection of monosomy 7 by GTG-banding and FISH in a patient with Shwachman-Diamond syndrome without evidence of myelodysplastic syndrome or acute myelogenous leukemia. 1059 42

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

We studied telomerase regulation and telomere length in hematopoietic progenitor cells from peripheral blood and bone marrow from patients with acute and chronic leukemia and myeloproliferative diseases. CD34+ cells from a total of 93 patients with either acute myeloid leukemia (AML; n = 25), chronic myeloid leukemia (CML; n = 21), chronic lymphocytic leukemia (CLL; n = 18), polycythemia vera (PV; n = 16), or myelodysplastic syndromes (MDS; n = 13) were analyzed before and in 19 patients after ex vivo expansion in the presence of multiple cytokines (kit ligand, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor plus erythropoietin). Compared with hematopoietic progenitor cells from normal donors (n = 108), telomerase activity (TA) was increased 2- to 5-fold in chronic phase (CP)-CML, CLL, PV, and MDS. In AML, accelerated phase (AP) and blastic phase (BP)-CML, basal TA was 10- to 50-fold higher than normal. TA of CP-CML CD34+ cells was up-regulated within 72 h of ex vivo culture, peaked after 1 week, and decreased below detection after 2 weeks. In contrast, TA in AP/BP-CML and AML CD34+ cells was down-regulated after 1 week of culture and decreased further thereafter. The expansion potential of CD34+ cells from patients with leukemia was considerably decreased compared with CD34+ cells from normal donors. The average expansion of cells from leukemic individuals was 6.5-, 2.3-, 0.6-, and 0.2-fold in weeks 1, 2, 3, and 4, respectively, whereas expansion of normal cells was 5- to 15-fold higher. In serial expansion culture, a median telomeric loss of 0.7 kbp was observed during 3-4 weeks of expansion. Our results demonstrate that up-regulation of telomerase is similar in CD34+ cells from CP-CML, CLL, PV, and MDS patients and in normal hematopoietic cells during the first week of culture, whereas in AML and AP/BP-CML, telomerase is high at baseline and down-regulated during expansion culture. High levels of telomerase in leukemic progenitors at baseline may be a feature of both the malignant phenotype and rapid cycling. Telomerase down-regulation during culture of leukemic cells may be due to the decreased expansion potential or repression of normal hematopoiesis, or in AML it may be due to the partial differentiation of AML cells, shown previously to be associated with loss of TA. Telomere shortening during ex vivo expansion correlated with low levels of TA, particularly in chronic leukemic and MDS progenitors where telomerase was insufficient to protect against telomere bp loss during intense proliferation.
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PMID:Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture. 1067 44

The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML-M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60-kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90-kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)-positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150-kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150-kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)-positive MDS/AML. Genes Chromosomes Cancer 27:229-238, 2000.
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PMID:Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21). 1067 11

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

Rearrangements affecting chromosome band 3q21 are observed in a subgroup of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, little is known about the molecular consequences of such aberrations. We therefore established a PAC contig in the 3q21 breakpoint region and identified potential protein coding sequences by exon trapping. One of the exons isolated was from the human GATA-2 gene, which we showed to be transcribed from telomere to centromere. The majority of 3q21 breakpoints are located telomeric to the transcribed portion of this gene in a region that in mice appears to be necessary for proper promoter function. Results of GATA-2 expression analyses in leukemic cell lines as well as primary patient samples are compatible with the hypothesis that 3q21 aberrations contribute to leukemogenesis through deregulation of the hematopoietic transcription factor GATA-2.
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PMID:Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia. 1087 93

The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), which is frequently characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and poor prognosis. Previously, the breakpoint cluster region (BCR) at 3q21 was identified within a 60-kilobase (kb) region centromeric to the BCR of 3q21q26 syndrome and that at 1p36.3 within a 90-kb region. In this study, genes were searched near the breakpoints at 1p36.3, and a novel gene was isolated that encoded a zinc finger protein with a PR domain, which is highly homologous to the MDS1/EVI1 gene. The novel gene, designated as MEL1 (MDS1/EVI1-like gene 1), with 1257 amino acid residues is 64% similar in nucleotide and 63% similar in amino acid sequences to MDS1/EVI1 with the same domain structure. The MEL1 gene is expressed in leukemia cells with t(1;3) but not in other cell lines or bone marrow, spleen, and fetal liver, suggesting that MEL1 is specifically in the t(1;3)(p36;q21)-positive MDS/AML. On the basis of the positional relationship between the EVI1 and MEL1 genes in each translocation, it was suggested that both genes are transcriptionally activated by the translocation of the 3q21 region with the Ribophorin I gene. Because of the transcriptional activation of the EVI1 family genes in both t(1;3)(p36;q21)-positive MDS/AML and 3q21q26 syndrome, it is suggested that they share a common molecular mechanism for the leukemogenic transformation of the cells.
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PMID:A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. 1105 5

One of the most common structural rearrangements in myelodysplastic syndrome (MDS) is a deletion of the long arm of chromosome 5, del(5q). The 5q- syndrome is a distinct entity, that presents with specific morphologic abnormalities of the megakaryocytic lineage. Thus, we evaluated the presence or absence of the del(5q) in these cells. We performed fluorescence in situ hybridization analysis using unique sequence probes (one for 5q31, the other for the 5p telomeric band), and tested bone marrow specimens from 10 patients with MDS (including 6 patients with the 5q- syndrome) and a del(5q). Megakaryocytes were identified by nuclear morphology, size, and ploidy index. Our results demonstrate the presence of the del(5q) in the megakaryocytic lineage and, thus, the involvement of these cells in the disease process.
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PMID:Deletion of 5q31 is observed in megakaryocytic cells in patients with myelodysplastic syndromes and a del(5q), including the 5q- syndrome. 1106 80

Chromosome 7 abnormalities are observed in a wide range of myeloid disorders, particularly myelodysplasia (MDS) and acute myeloid leukaemia (AML). Monosomy 7 and 7q deletions are the most frequent abnormalities, although translocations and inversions involving 7q also occur. The region 7q22--q34 may contain as many as four distinct minimal regions of deletion (MDRs), which are thought to contain one or more myeloid tumour-suppressor genes. We have defined previously the proximal breakpoint of a constitutional 7q22--q34 inversion, carried in a cell line derived from a member of a family with a history of MDS. A YAC clone spanning this breakpoint was identified. Both inversion breakpoints have now been cloned and sequenced, placing the proximal breakpoint 40 kb centromeric to the TAC2 (tachykinin 2) gene and the distal breakpoint 42 kb telomeric to the SSBP (mitochondrial single-stranded DNA-binding protein) gene. Sequence alignments revealed small (3--4 bp) duplications at the inversion breakpoints, suggesting that the mechanism of inversion involved the creation of staggered breaks and filling in of the overhanging ends. A 190-bp Alu--Alu deletion close to the distal breakpoint was also detected and may have contributed to the inversion.
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PMID:Molecular characterization of a myelodysplasia-associated chromosome 7 inversion. 1132 94

Deletions or monosomy of chromosomes 5 and 7 are frequently observed in myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). In this study two genes, PURA and PURB, encoding functionally cooperative proteins in the Pur family, are localized to chromosome bands 5q31.1 and 7p13, respectively. One or both of these loci are shown to be hemizygously deleted in 60 MDS or AML patients using fluorescence in situ hybridization (FISH). High-resolution mapping of PURA localizes it approximately 1.1 Mb telomeric to the EGR-1 gene. Frequency of PURA deletion and segregation with EGR-1 indicate that PURA is within the most commonly deleted segment in myeloid disorders characterized by del(5)(q31). No mutations have been detected within the coding sequence of PURA. Concurrent deletions of PURA and PURB occur in MDS at a rate nearly 1.5-fold higher than statistically expected and in AML at a rate > 5-fold higher. This novel simultaneous deletion of two closely related gene family members may thus have consequences related to progression to AML. Pur alpha, an Rb-binding protein, has been implicated in cell cycle control and differentiation, and Pur alpha and Pur beta are reported to function as heterodimers. Alterations in these genes could affect a delicate balance critical in myeloid development.
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PMID:Deletions of PURA, at 5q31, and PURB, at 7p13, in myelodysplastic syndrome and progression to acute myelogenous leukemia. 1141 83


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