Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: KEGG:D03343 (MDS)
 2,225 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.
 ...
PMID:[Activation of protooncogenes by point mutations in hematological malignancies]. 151 54

The myelodysplastic syndrome is a paradigm of human preleukaemia. Normal haemopoiesis is progressively displaced by an abnormal clone derived from a mutated stem cell. The initial mutation is unknown but its occurrence may be related to the overall load of random mutations which are a consequence of both intrinsic DNA defects and external mutagens. Evolution of the pathological population is marked by an increasing load of genetic lesions at the molecular and cytogenetic levels. Ras mutations can be detected in the blood of about 50% of MDS patients. Fms mutations are less common but these lesions can be found both in patients and in haematologically normal subjects who have previously received cytotoxic therapy suggesting that they can occur early in the preleukaemic process. Clonal haemopoiesis in the absence of either ras or fms mutations can occur in these subjects. The data suggest the inability of mutant ras or fms genes alone to produce observable preleukaemic changes but that subjects with these mutations may be predisposed to future MDS. Ras mutations are a common accompaniment of a wide variety of malignancies and experimental transfection of the mutant gene can induce a malignant phenotype in cultured cells. There are many possible mechanisms for this transformation which may be relevant in a clinical context. Experimentally observed effects include a direct influence on the cell cycle, the induction of drug resistance and the stimulation of autocrine growth factor production. It may eventually be possible to define which gene mutations are important in conferring a malignant state, which determine phenotype and which are of incidental significance.
 ...
PMID:Gene mutations in myelodysplasia. 173 70

ras gene mutations are the most frequent molecular changes found in the preleukemic syndromes of adults and may play a role in initiating these diseases and in their progression to acute leukemia. However, little is known about the incidence or importance of these genetic mutations in childhood myeloproliferative states (MPS). The bone marrow (BM) monosomy 7 syndrome accounts for a large percentage of childhood MPS. Although the duration of the MPS is quite variable, children with monosomy 7 eventually develop acute myeloid leukemia (AML). We investigated 20 children (13 with MPS, 7 with AML) with BM monosomy 7 or 7q- for the presence of ras gene mutations using the polymerase chain reaction and hybridization with mutation-specific oligonucleotides. Mutations of N-ras and K-ras were detected in three children. Two patients carrying a ras mutation were in the myeloproliferative phase, and one had acute leukemia. All three patients with ras mutations either died of their disease or relapsed after BM transplantation as compared with 8 of 17 without ras mutations. However, this difference is not statistically significant (P = .14, not significant). We conclude that ras mutations are observed in childhood monosomy 7, though less frequently than in adult MDS, and may play a limited role in the progression of this disease to acute leukemia. More patients are needed to address the prognostic role of ras mutations in this rare disease.
 ...
PMID:Mutations of the ras proto-oncogenes in childhood monosomy 7. 199 Nov 70

Abnormalities of the short arm of chromosome #12 (12p) were found in 18 patients, 7 with previously untreated acute nonlymphocytic leukemia (ANLL) and 11 with dysmyelopoietic syndromes (MDS) or ANLL following treatment for another malignant disease. The chromosome #12 abnormality was a partial deletion in 15 patients and a translocation in 3. The 12p- was the sole chromosomal abnormality in seven patients (four with de novo ANLL) and was associated with other chromosome abnormalities in eight patients. Thus, partial monosomy for 12p was often associated with other chromosomal changes and was a secondary abnormality in some cases. The consequences of this hemizygosity for genes located at 12p are discussed with references to the possible expression of a potentially mutated recessive gene. The study of c-K-ras 2, normally located at 12p, must be done in such cases, as the association of secondary blood disorders and multiple chromosome abnormalities suggests a possible mutation of this c-oncogene on chromosome #12.
 ...
PMID:Abnormalities of the short arm of chromosome 12 in acute nonlymphocytic leukemia and dysmyelopoietic syndrome. 394 49

Karyotypic analysis was performed in a total of 69 patients with well-characterized idiopathic myelofibrosis. Karyotypic abnormalities were detected in 46% of cases examined during the chronic phase (29/63); with three abnormalities, del(13q), del(20q) and partial trisomy 1q, accounting for 75% of all abnormalities at diagnosis. The absence of del(5q), trisomy 8 and 21, as well as the rarity of monosomy 7, contrasts with pooled published data and may reflect our exclusion of closely related disorders, in particular MDS with fibrosis. Chromosomal aberrations increased to approximately 90% (8/9) in patients analysed during acute transformation. Mutational activation of codons 12, 13 and 61 of N-, Ha- and Ki-ras genes were assessed by polymerase chain reaction and hybridization with synthetic non-radioactive digoxigenin-labelled probes. Three mutations were detected in samples of peripheral blood DNA taken from 50 patients during the chronic phase of their disease: one N12 Asp (GGT-->GAT) and two N12 Ser (GGT-->AGT) mutations. The results from this study indicate that karyotypic abnormalities are present in at least 29% of cases at diagnosis and that del(13q), del(20q) and partial trisomy 1q are the most frequent findings. Ras mutations were relatively infrequent (6%) and appeared restricted to the N-ras gene. Karyotypic analysis at diagnosis was found to be of prognostic significance.
 ...
PMID:Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis. 781 70

Most studies of the clonal origin of the underlying lesion(s) and all investigations using X-inactivation, have concluded that the myelodysplastic syndromes arise from a multipotent stem cell. Non-random chromosomal abnormalities, particularly deletions of 5q and 7q, are common, most notably in therapy related MDS. Progression to AML is also frequently accompanied by increased genomic instability as evidenced by the emergence of multiple karyotypic abnormalities. While some evidence hints at the presence of tumour suppressor genes on chromosomes 5, 7, 20 and 12, no such genes have yet been identified. The search for point mutations in known oncogenes has concentrated on two oncogenes RAS and c-FMS. Point mutation frequency generating active forms of RAS oncogenes is approximately 40% in MDS overall, up to 80% in studies of CMML. 60% of all MDS RAS mutation involves a G to A transition, producing a substitution of aspartate for glycine at a frequency of 50% (of total ras mutants). RAS mutation is associated with progression to AML, although the presence of a RAS point mutation alone is neither necessary nor sufficient for leukaemic transformation. Mutation of c-FMS is also more common in CMML in comparison to other MDS subtypes and, as yet, point mutation potentiating the response of the receptor to CSF-1 (codon 969) has been found more frequently than point mutation resulting in permanently activated receptor (codon 301). However, recent work has identified additional mutations which produce transforming proteins, and mutation rates at these sites may be relevant in MDS.
 ...
PMID:Myelodysplastic syndromes: from morphology to molecular biology. Part II. The molecular genetics of myelodysplasia. 849 99

Although molecular and cytogenetic studies strongly point to the role of oncogenes, the mechanisms underlying the development of MDS and their progressive evolution to AML are still largely unknown. It has been postulated that AML has a preleukemic stage and a multi step pathogenesis, with the preleukemic stem cell able to undergo clonal evolution, with the acquisition of karyotypic abnormalities, leading to the development of acute leukemic subclones. The activations of the ras oncogenes or inactivation of the p53 anti-oncogene by point mutations have been described recently in several cases of MDS as well as AML, suggesting a critical role for these alterations in the development of these myelogenous leukemias. We reported previously establishment of a leukemic cell line, SKM-1, from the patient who initially possessed multiple point mutations of ras genes but lost these mutations during disease progression to myelomonocytic leukemia with acquisition of chromosomal abnormalities involving the p53 anti-oncogene. This process is characterized by genetic instabilities probably due to the failure of their DNA repairment leading to abnormal control of cell proliferation and differentiation. Studying this cell line, SKM-1, is a promising approach to understand the mechanisms of the initiation, disease progression, alterations of DNA repairment, and genetic instability in MDS and myelogenous malignancies.
 ...
PMID:The SKM-1 leukemic cell line established from a patient with progression to myelomonocytic leukemia in myelodysplastic syndrome (MDS)-contribution to better understanding of MDS. 858 Aug 5

Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome-refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of other de novo and therapy-related MDS and acute myeloid leukemia (AML) types, most often in association with other chromosome abnormalities. However, the loss of genetic material from 5q is believed to be of primary importance in the pathogenesis of all del(5q) disorders. In the present study, we performed fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific whole chromosome painting probe and a 5q subtelomeric probe to determine the incidence of cryptic translocations. We studied archival fixed chromosome suspensions from 36 patients with myeloid disorders (predominantly MDS and AML) and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a translocation of 5q subtelomeric sequences from the del(5q) to the short arm of an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping confirmed that the 5q and 11p translocation breakpoints were the same in all 3 cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4) genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin pseudogene (RDPX1) on 11p15.5. Importantly, all 3 patients with the cryptic t(5;11) were children: a total of 3 of 4 AML children studied. Two were classified as AML-M2 and the third was classified as M4. All 3 responded poorly to treatment and had short survival times, ranging from 10 to 18 months. Although del(5q) is rare in childhood AML, this study indicates that, within this subgroup, the incidence of cryptic t(5;11) may be high. It is significant that none of the 24 MDS patients studied, including 11 confirmed as having 5q-syndrome, had the translocation. Therefore, this appears to be a new nonrandom chromosomal translocation, specifically associated with childhood AML with a differentiated blast cell phenotype and the presence of a del(5q).
 ...
PMID:A new recurrent translocation, t(5;11)(q35;p15.5), associated with del(5q) in childhood acute myeloid leukemia. The UK Cancer Cytogenetics Group (UKCCG) 1039 45

Granulocyte colony-stimulating factor (G-CSF) has had a major impact on the management of "severe chronic neutropenia" (SCN), a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia and Shwachman-Diamond syndrome (SDS) have developed myelodysplastic syndrome and acute myeloid leukemia (MDS/AML), which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. To address this, the Severe Chronic Neutropenia International Registry (SCNIR) used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. In murine models, the latter produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. Since congenital neutropenia and SDS are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an "innocent bystander" that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. In patients who transform to overt MDS or AML, hematopoietic stem cell transplantation is the only chance for cure. In those with "soft" signs of MDS, such as an isolated clonal cytogenetic change but without other evidence of MDS, or with an isolated G-CSF receptor mutation, there is room for conservative management. One option is to reduce the G-CSF dosage as much as possible, and observe the tempo of progression, if any, to more overt signs of malignancy.
 ...
PMID:Risk of myelodysplastic syndrome and acute myeloid leukemia in congenital neutropenias. 1195 96

Large studies have shown that, in MDS, main prognostic factors for survival and progression to AML were the percentage of bone marrow blasts, the number and importance of cytopenias, and the presence of cytogenetic abnormalities. The combination of those 3 factors has yielded an International Prognostic Scoring System (IPSS), with very strong prognostic value for survival and progression to AML, which can therefore be used as a guideline for therapeutic choices. Other important prognostic factors can be derived from molecular studies. They include ras genes mutations, p53 mutations and p15 hypermethylation, but their independent prognostic value remains uncertain.
 ...
PMID:[Prognostic factors in myelodysplasia syndromes]. 1208 70


1 2 Next >>