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)

We report two cases of hematological malignancies, comprising a case of myelodysplastic syndrome (MDS) that rapidly evolved into acute myeloid leukemia, and a case of myeloproliferative disorder (MPD), in which der(1;18)(q10;q10) was found as the sole acquired karyotypic abnormality. This observation indicates that the unbalanced translocation is a recurrent aberration in myeloid disorders. To the best of our knowledge, centromeric fusion between long arms of chromosomes 1 and 18, leading to a normal chromosome 18 substituted with a der(1;18) chromosome, is novel and has not been described in cancer. Mechanistically, either trisomy 1q or monosomy 18p that results from the translocation may potentially contribute to leukemogenesis. Finally, chromosomes with large constitutive heterochromatin bands such as chromosome 1 may be at risk of centromeric instability and be predisposed to centromeric fusion with other chromosomes.
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PMID:Derivative (1;18)(q10;q10): a recurrent and novel unbalanced translocation involving 1q in myeloid disorders. 1145 27

Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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PMID:Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias. 1145 19

Eighty-two unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) were investigated for internal tandem duplications of the FLT3 gene (FLT3/ITD), for internal tandem duplications of the MLL gene (MLL/ITD) and for mutations of the WT1 gene. FLT3/ITD were observed in three patients, another two patients presented MLL/ITD whereas mutations of the WT1 gene were not observed. All FLT3/ITD included the tyrosine-rich stretch between codons 589 and 599, and both MLL/ITD presented break points within Alu-repeats, as previously observed in de novo AML. The ITD were not related to any specific type of previous therapy, but three out of the five cases were observed among only six patients with overt t-AML and a normal karyotype (P = 0.0043). Interestingly, one of the patients with FLT3/ITD presented overt t-AML of subtype M1 with a normal karyotype after treatment with an alkylating agent. Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present. Thus FLT3/ITD may in this case represent a primary event in leukemogenesis, whereas the t(15;17) may represent a secondary event most likely induced by subsequent therapy. In conclusion, FLT3/ITD and MLL/ITD are mainly observed in uncharacteristic cases of t-AML with a normal karyotype and unrelated to previous therapy for which reason they could represent sporadic cases of de novoAML.
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PMID:Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. 1175 4

It has been demonstrated that the chromosomal translocation t(7;11)(p15;p15) in patients with human acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) invariably involves fusion of the nucleoporin gene, NUP98, on chromosome 11 and the class 1 HOX gene, HOXA9, on chromosome 7, and that the fusion gene NUP98-HOXA9 is an important gene in myeloid leukemogenesis. Here are reported 2 novel chromosome 7p15 targets of the t(7;11)(p15;p15) chromosomal translocation in 2 patients with CML and myelodysplastic syndrome (MDS). Southern blot and polymerase chain reaction (PCR) analyses of leukemia cell DNA failed to show rearrangement of HOXA9, whereas NUP98 was found to be rearranged in both cases. Reverse transcription-PCR analysis using a NUP98 primer and a degenerate primer corresponding to the third helix of the homeodomain of HOXA demonstrated that NUP98 was fused in-frame to HOXA11 in the patient with CML and to HOXA13 in the patient with MDS. The chromosomal breakpoints on 7p15 were located within introns of HOXA11 or HOXA13 genes. In both patients chimeric NUP98-HOXA9 transcripts were also observed. These findings suggest that AbdB-type HOXA genes are common targets of t(7;11)(p15;p15) chromosomal translocations and that a single translocation can produce more than one NUP98-HOXA fusion gene, presumably because of altered splicing.
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PMID:Single-translocation and double-chimeric transcripts: detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(p15;p15). 1183 Apr 96

Cytogenetic studies can be useful in the clinical management of patients with leukemia. They may also give a clue to leukemogenesis and/or pathogenesis. Numerous disease-specific chromosomal aberrations have been and continue to be identified. Translocation (1;19)(q21 through q23;p13.3) involving the long arm of chromosome 1 and the short arm of chromosome 19 is usually associated with acute lymphoblastic leukemia. We found a new translocation involving one virtually identical breakpoint 19p13 and one distinct 1p13 in two cases of myeloid neoplasms. Studies of bone marrow and peripheral blood specimens specified in one of our patients acute myeloid leukemia and in an other myelodysplastic syndrome. Conventional cytogenetics was supplemented by spectral karyotyping (SKY), microdissection, and fluorescence in situ hybridization. Our first case showed a der(1)t(1;19)(p13;p13.1) as the sole chromosomal change. In addition to this translocation, a pericentric inversion within chromosome 10 and with a cryptic t(10;11) were detected by SKY in the second case. Translocation (1;19)(p13;p13.1) may play a role in the leukemogenesis of myeloid diseases.
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PMID:Novel der(1)t(1;19) in two patients with myeloid neoplasias. 1189 Sep 91

Deletions of chromosomes 17 and 20 are well-described abnormalities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) but translocations involving these two chromosomes are uncommon. We present five male patients, one with MDS and four with AML, in whom a new, nonrandom unbalanced dicentric t(17;20), resulting in deletions of 17p and 20q, was identified. Conventional cytogenetics showed additional karyotypic abnormalities in most of the patients, including deletions of 5q, deletions or monosomy of chromosome 7, and deletions of 18q. Fluorescence in situ hybridization showed a deletion of the tumor suppressor gene TP53 on 17p. Of the four cases with follow-up data available, only two had received combination chemotherapy. Overall survival in these two cases was 6 and 7 weeks, respectively. Two other patients who had no active therapy administered died 6 weeks and 9 months after diagnosis, respectively. These five cases highlight a rare but recurrent abnormality in MDS and AML, potentially involving genes on 17p and 20q of importance in myeloid leukemogenesis.
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PMID:A new nonrandom unbalanced t(17;20) in myeloid malignancies. 1241 82

Myelodysplastic syndromes (MDS) are considered to be a family of clonal disorders of hematopoietic stem cells that are characterized by ineffective hematopoiesis and susceptibility to acute myelogenous leukemias, and are shown to be strikingly refractory to current therapeutic modalities. A substantial proportion of these complex diseases arise in the setting of exposures to environmental or occupational toxins, including cytotoxic therapy for a prior malignancy or other disorder. The conversion of a normal stem cell into a preleukemic and ultimately leukemic state is a multistep process requiring the accumulation of a number of genetic lesions. On the genomic level, MDS is typified by losses and translocations involving certain key gene segments, with disruption of the normal structure and function of genes that control the balance of proliferation and differentiation of hematopoietic precursors. More than a half of the chromosomal abnormalities in MDS comprise deletions of chromosomes 5, 7, 11, 12, 13 and 20. This evidence suggests that as yet unidentified tumor suppressor genes should have important roles in the molecular mechanisms of MDS. Further molecular approaches to such genetic lesions will identify the relevant tumor suppressor genes. Over the past years, major signal transduction molecules were identified and their genetic alterations were extensively analyzed in MDS as well as leukemias. These include receptors for growth factors, RAS signaling molecules, cell cycle regulators, and transcription factors. Among them, notable is transcription factors that regulate both proliferation and differentiation of hematopoitic stem cells. The disruption of the normal flow of the signal transduction pathways involving these molecules translates into ineffective multilineage hematopoiesis and bone marrow failure. Therefore, MDS provides a fertile testing ground on which we could study the molecular dissection implicated in the multistep leukemogenesis.
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PMID:Molecular pathogenesis of MDS. 1243 Sep 28

Hydroxyurea is an established drug that has been used for the treatment of myeloproliferative disorders and some solid tumors for some time. In recent years it has also been found to be effective in the treatment of sickle cell disease. Short term side effects are not serious, and are manageable. The major concern is the potential leukemogenesis with long term use. The risk of leukemogenesis is not defined with its use in benign hematological conditions. We report a case of acute myeloid leukemia with no preceding myelodysplastic syndrome, occurring after 2 years of hydroxyurea therapy in a patient with sickle cell disease.
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PMID:Are we underestimating the leukemogenic risk of hydroxyurea. 1250 8

The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the beta subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.
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PMID:New mechanisms of AML1 gene alteration in hematological malignancies. 1252 54

Trisomy 8 is the most common chromosomal aberration in myelocytic malignancies, occurring both as a sole change as well as in addition to other abnormalities. In spite of this, next to nothing is known about its pathogenetic importance or its molecular genetic consequences. Possible mechanisms involved in the transformation process include dosage effects of genes mapping to chromosome 8 and presence of specific mutations or cryptic fusion genes on the duplicated chromosome. In the latter case, +8 would be secondary to a cryptic primary rearrangement and not involved in leukemogenesis as such, but rather in tumor evolution. Although hidden genetic changes have been found in some trisomies, for example, mutations in KIT in acute myelocytic leukemia (AML) with +4 and in MET in hereditary papillary kidney carcinoma with trisomy 7, none associated with +8 have so far been discovered. To address this issue, we have investigated a total of 13 cases of AML, myelodysplastic syndromes, and chronic myeloproliferative disorders with trisomy 8 as the sole chromosomal anomaly. All cases were studied by combined binary ratio multicolor fluorescence in situ hybridization (FISH) and with FISH using locus-specific probes for both arms of chromosome 8, the subtelomeric regions of 8p and 8q, and the leukemia-associated genes FGFR1, MOZ, ETO, and MYC. No cryptic changes were detected, thus excluding the possibility of gross genetic rearrangements or aberrations involving these loci on chromosome 8.
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PMID:Trisomy 8 as the sole chromosomal aberration in myelocytic malignancies: a multicolor and locus-specific fluorescence in situ hybridization study. 1449 2


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