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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

These two issues of the Seminars in Hematology will provide the physician the necessary knowledge to help make sense of this somewhat confusing array of diseases. The subdivisions of MDS reflect the precision of our techniques of dissection, with morphological and histochemical analyses forming the foundation to identify and subdivide MDS. Although steady refinement has occurred over the last half-century, the basic morphologic technique is unchanged. Cytogenetic analysis, which has been possible since the 1960s and 1970s, should be done at least at initial presentation in all patients to provide refinement of diagnosis and prognosis. FISH is not, at this time, useful as a screening technique. Although the 1990s is an era of rapidly growing knowledge and technical abilities in molecular biology, the use of these techniques in MDS is in its infancy. Very few genes have been identified which are altered in MDS, although many must exist. The molecular assays continue to be cumbersome and impractical to use in the clinical laboratory and remain the domain of the research scientist. Nevertheless, in the future, molecular biology will enable the internist to give each individual a clearer diagnosis and prognosis and may even provide targetted therapies of patients with MDS. At this time the center of management is good supportive care. Some patients, however, will benefit from special interventions, which include the use of growth factors, BMT, and in selected patients, aggressive chemotherapy. Induction of differentiation of the abnormal hematopoietic clone remains only a dream, although some of the differentiation agents may have applicability for their ability to induce apoptosis and prevent growth of the MDS clone of cells. Many of the major advances in our knowledge of cancer developed through the study of hematopoietic malignancy. A lot of these advances are due to the ease of obtaining the abnormal cells. MDS provides an excellent model for studying the progression of cells from their normal to preneoplastic and fully transformed states. A lucid understanding of this progression can form the paradigm for basic science to study neoplastic progression, and the molecular biology techniques used for these studies will be the basic tools used by hematologists and oncologists in the future.
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PMID:Myelodysplastic syndromes. 872 80

Loss of chromosome 7 (-7) or deletion of its long arm (7q-) are recurring chromosome abnormalities in myeloid disorders, especially in therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML). The association of -7/7q- with myeloid leukemia suggests that these regions contain a novel tumor suppressor gene(s) whose loss of function contributes to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified: one in band 7q22 and a second in bands 7q32-q35. We analyzed bone marrow and blood samples from 21 patients with myeloid leukemia (chronic myeloid leukemia, n = 2; de novo MDS, n = 4; de novo AML, n = 13; t-AML, n = 2) that on chromosome banding analysis exhibited deletions (n = 19) or reciprocal translocations (n = 2) of band 7q22 using fluorescence in situ hybridization. As probes, we used Alu-polymerase chain reaction products from 22 yeast artificial chromosome (YAC) clones that span chromosome bands 7q21.1-q32, including representative clones from a panel of YACs recognizing a contiguous genomic DNA fragment of 5 to 6 Mb in band 7q22. In the 19 cases with deletions, we identified two distinct commonly deleted regions: one region within band 7q22 was defined by the two CML cases; the second region encompassed a distal part of band 7q22 and the entire band 7q31 and was defined by the MDS/AML cases. The breakpoint of one of the reciprocal translocations was mapped to 7q21.3, which is centromeric to both of the commonly deleted regions. The breakpoint of the second translocation, which was present in unstimulated bone marrow and phytohemagglutinin-stimulated blood of an MDS patient, was localized to a 400-kb genomic segment in 7q22 within the deletion cluster of the MDS/AML cases. In conclusion, our data show marked heterogeneity of 7q22 deletion and translocation breakpoints in myeloid leukemias, suggesting the existence of more than one pathogenetically relevant gene.
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PMID:Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias. 905 25

During the period from 1995 to 1997, we studied 19 new cases of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML), extending our series to 180 consecutive cases: 123 patients with t-MDS and 57 patients with t-AML. Cytogenetically unrelated clones were observed in 13 patients: 11 patients with two unrelated clones, one patient with three unrelated clones, and one patient with four unrelated clones. Twelve cases of unrelated clones presented as t-MDS, whereas only one case presented as overt t-AML. Partial or complete deletions of the long arms or monosomy for chromosome 5 or chromosome 7, which are characteristic of t-MDS and t-AML, were observed in both unrelated clones in four patients and in one unrelated clone only in six patients, whereas three patients showed aberrations in both clones that were uncharacteristic of t-MDS or t-AML. Three different interpretations of the origin and significance of cytogenetically unrelated clones in t-MDS and t-AML are presented, although the disease is still considered to be monoclonal. First, patients with different defects of the long arm of chromosome 5 or chromosome 7 in two unrelated clones often seem to have acquired these aberrations as independent events. For this reason, it is possible that they may play an important role in leukemic transformation, for instance, by activating or potentiating the effect of a genetic change that is present in all cells but not disclosed as a visible chromosome abnormality. In cases with involvement of other chromosomes, unrelated clones sometimes develop by cytogenetic change in only a subclone of cells, indicating that they play a role only in tumor progression. Finally, unrelated clones in t-MDS and t-AML may represent two different monoclonal diseases: the primary tumor and t-MDS. This view is supported by the significant excess of unrelated clones observed in t-MDS following multiple myeloma (4 in 13 cases) compared with other diseases (9 in 167 cases; P = 0.02), and by results from a case with a balanced translocation that is highly characteristic of non-Hodgkin's lymphoma in one clone and a t-MDS-associated deletion of the long arm of chromosome 5 in another.
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PMID:Cytogenetically unrelated clones in therapy-related myelodysplasia and acute myeloid leukemia: experience from the Copenhagen series updated to 180 consecutive cases. 982 7

Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias. The association of -7/7q- with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS], n = 3; de novo acute myeloid leukemia [AML], n = 9; therapy-related (t-) AML, n = 1) which, on chromosome banding analysis, exhibited deletions (n = 12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (-7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.
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PMID:Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders. 983 5

Patients with secondary myelodysplasias and acute myeloid leukemias (MDS/AML) frequently exhibit interstitial deletions of the chromosome-5q resulting in hemizygous loss of the transcription transactivator Smad5. Smad5 is a member of the signal transducer family conveying the pleiotropic TGF-gb/BMP cytokine signals with roles in development, cell growth control, and tumor progression. Here we present a study of the Smad5 expression and its functional role in leukemia cell lines as well as in primary CD34+ progenitors of MDS/AML patients and healthy individuals. Consistent Smad5 gene expression in these cell types and the gradual increase in its mRNA and protein levels in a model of induced erythroid differentiation of murine erythroleukemia (MEL) cells suggest a role of the gene in hematopoiesis. We show that bone morphogenetic protein 4 (BMP4) directs Smad5 activation in human hematopoietic cells, as monitored at the levels of protein phosphorylation, nuclear translocation, and specific transcription response. In vitro induction of normal human CD34+ cells by BMP4 results in significantly increased proliferation of erythroid progenitors (BFU-E) and formation of glycophorin-A+ cells, whereas perturbation of Smad5 expression by antisense oligonucleotides causes significantly decreased rates of BMP4-induced erythroid differentiation. We have not detected any effects of Smad5 inhibition on BMP4-stimulated progenitors of the granulocyteNmacrophage lineage. We propose that the BMP4/Smad5 signal transduction pathway activates hematopoietic differentiation programs that may be impaired in anemia manifestations in MDS and AML patients with Smad5 haploinsufficiency.
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PMID:Inhibition of Smad5 in human hematopoietic progenitors blocks erythroid differentiation induced by BMP4. 1206 18

Foxp3(+) T regulatory cells (Tregs) and Th17 cells accumulate synchronously at tumor sites during cancer progression, where their interplay is apparently affecting the efficiency of the antitumor response. In myelodysplastic syndromes, a hematopoietic malignancy of myeloid origin, Tregs are highly increased in the late stages of the disease (L-MDS), but the mechanisms driving Treg expansion and the interaction between Treg and Th17 cell dynamics are still unknown. We demonstrate that the proliferative capacity of Tregs is deficient during the early MDS stages (E-MDS), while in L-MDS it returns to normal levels. In addition, synchronously to Treg expansion, L-MDS patients exhibit increased numbers of functionally competent bone marrow IL-17(+) and FOXP3(+)/IL-17(+) cells, in contrast to E-MDS patients, where Th17 cells are significantly decreased and hypofunctional. Our findings suggest similar kinetics of Treg and Th17 cells between MDS and solid tumors, indicating a common immune pathogenetic pathway between diverse cancer types.
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PMID:Th17 and Foxp3(+) T regulatory cell dynamics and distribution in myelodysplastic syndromes. 2144 47

Some studies show that alterations in expression of proteins related to mitotic spindle (AURORAS KINASE A and B) and mitotic checkpoint (CDC20 and MAD2L1) are involved in chromosomal instability and tumor progression in various solid and hematologic malignancies. This study aimed to evaluate these genes in MDS patients. The cytogenetics analysis was carried out by G-banding, AURKA and AURKB amplification was performed using FISH, and AURKA, AURKB, CDC20 and MAD2L1 gene expression was performed by qRT-PCR in 61 samples of bone marrow from MDS patients. AURKA gene amplification was observed in 10% of the cases, which also showed higher expression levels than the control group (p=0.038). Patients with normo/hypercellular BM presented significantly higher expression levels than hypocellular BM patients, but normo and hypercellular BM groups did not differ. After logistic regression analysis, our results showed that HIGH expression levels were associated with increased risk of developing normo/hypercellular MDS. It also indicated that age is associated with AURKA, CDC20 and MAD2L1 HIGH expression levels. The distinct expression of hypocellular patients emphasizes the prognostic importance of cellularity to MDS. The amplification/high expression of AURKA suggests that the increased expression of this gene may be related to the pathogenesis of disease.
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PMID:Proteins related to the spindle and checkpoint mitotic emphasize the different pathogenesis of hypoplastic MDS. 2431 88