Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A nonrandom translocation between chromosomes 3 and 21, t(3;21)(q26.2;q22) has been detected in patients with a myelodysplastic syndrome or acute myeloid leukemia after treatment (t-MDS/t-AML) for a primary malignant disease and in chronic myelogenous leukemia in blast crisis (CML-BC). In these patients, the breakpoint on chromosome 21 is at band 21q22. This band is also involved in the t(8;21)(q22;q22) detected in 40% of the patients with acute myeloid leukemia subtype M2 (AML-M2) de novo who have an abnormal karyotype. In the t(8;21), the AML1 gene is the site of the breakpoint on chromosome 21. The AML1 gene is transcribed from telomere to centromere, and in the t(8;21) the 5' part of AML1 is fused to the ETO gene on chromosome 8 to produce the chimeric AML1/ETO on the der(8) chromosome. We found that AML1 is also rearranged in two t-AML patients and in one CML-BC patient with the t(3;21), but the breakpoints are approximately 40 to 60 kb downstream to those of AML-M2 patients. This region contains at least one additional exon of AML1, as determined by using an AML1 cDNA as a probe in Southern blot analysis. The t(3;21) breakpoints for the remaining patients could not be determined because, by fluorescence in situ hybridization analysis, the breaks are outside of the region covered by the available probes.
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PMID:Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. 849 Jan 81

Donor mononuclear cell (MNC) infusions provide a very potent and effective anti-leukemic therapy. For patient's with CML who relapse after allogeneic BMT, the administration of donor MNC can result in a direct GVL effect and re-establish sustained remissions, even when assessed by very sensitive PCR-based techniques. The GVL reaction appears to be most prominent in patients with chronic phase CML. It is less apparent for patients with more advanced stages of CML or for patients with relapsed acute leukemia and myelodysplasia, although only small numbers of these patients have been treated. While the majority of patients tolerate this therapy very well, treatment related morbidity and mortality is still quite significant, and efforts to limit the severity of GVHD, and to recognize and treat marrow aplasia early may be useful. Longer follow-up of patients who have achieved complete remission will be required to determine if this therapy will have an impact on long term disease free survival, but at the current time, it would seem to be a very acceptable alternative to a second BMT.
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PMID:Adoptive immunotherapy for relapsed leukemia following allogeneic bone marrow transplantation. 858 Jul 87

The FAB group has recently published guidelines for distinguishing chronic granulocytic leukaemia (CGL) from chronic myelomonocytic leukaemia (CMML) and atypical chronic myeloid leukaemia (aCML). Whereas CGL is generally recognized to be a distinct entity, there is debate as to whether CMML and aCML are separate disorders or part of a spectrum of myeloproliferative disorders with dysplastic features. Data are presented on 10 cases who developed features of a CML during the course of their disease but who presented with a normal or a low leucocyte count without a monocytosis and were diagnosed as refractory anaemia. This suggests that, at least in some cases, aCML represents an unusual evolution of MDS, and even though these patients have a uniformly poor prognosis it may be premature to regard aCML as a distinct clinical entity.
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PMID:Atypical chronic myeloid leukaemia, a distinct clinical entity related to the myelodysplastic syndrome? 861 21

Evi-1 is a transforming gene originally identified in a common integration site of murine leukemia retrovirus and mapped in human chromosome 3q26. It is not normally expressed in either human or murine hematopoietic cells, but is overexpressed in retrovirus-induced murine myeloid leukemias as well as human myeloid leukemias with 3q26 abnormalities, and thus thought to be responsible for both human and murine leukemogenesis. In this study, possible involvement of the Evi-1 gene in human leukemias was evaluated by Northern blot analysis in a total of 73 patients with various types of leukemias. We found that increased expression of the Evi-1 gene was most frequently observed in patients with CML in blastic crisis. It was found in 10 of 14 (71.0%) samples from CML in blastic crisis, three of 15 (20.0%) from acute myelocytic leukemia, three of 11 (27.3%) from MDS-derived leukemia, and one of 11 (9.1%) from acute lymphoblastic leukemia. Among 18 patients showing increased Evi-1 expression, none of 17 informative patients showed cytogenetic abnormalities involving 3q26. In addition, Southern blot analysis revealed neither amplification nor rearrangements of the Evi-1 gene in 11 Evi-1-positive patients whose DNA samples were available. Our results suggest that increased expression of the Evi-1 gene may play an important role in development of human leukemias, especially in progression from chronic phase to blastic crisis of CML even without 3q26 abnormalities.
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PMID:Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia. 865 73

In a retrospective analysis we assessed occurrence, contributing factors and outcome of patients experiencing granulocytic sarcoma as a localized extramedullary relapse after allogeneic BMT. EBMT members were asked to report the number of patients transplanted for leukemia between January 1981 and December 1992 and the number of patients with granulocytic sarcoma. Of a total of 5824 patients transplanted for AML, CML or MDS by 86 teams, granulocytic sarcoma was observed in 26 patients (0.45% occurring 4-56 months after BMT. Granulocytic sarcoma occurred after allogeneic BMT in 20 out of 3071 patients grafted for AML (0.65%), and in the CML/MDS subgroup in six out of 2753 grafted patients (0.22%). Granulocytic sarcoma can involve any site of the body, presenting as a soft tissue mass; it occurred in body cavities (eg pleural cavity, abdominal cavity, spinal canal, stomach and bladder), the head and neck region (orbit, ear, skull base, peripheral nerves), the trunk and limbs, and mammary and sex glands. Granulocytic sarcoma predicts an additional hazard to outcome after BMT. Nine of 26 patients (33%) were alive 15-151 months after the onset of granulocytic sarcoma. Advanced disease stage at grafting adversely affected survival and all patients died. The best treatment option still needs to be defined.
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PMID:Granulocytic sarcoma after allogeneic bone marrow transplantation: a retrospective European multicenter survey. Acute and Chronic Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. 873 1

Soluble receptors have been identified for most members of the TNF-receptor/NGF receptor superfamily. CD95 (Fas/Apo-1) is of particular importance, since its triggering may induce apoptosis in sensitive cells. Recently, a soluble form of the CD95 molecule was described which interacts with the CD95-CD95 ligand death pathway. Increased concentrations of soluble CD95 (sCD95) were previously detected in some patients with T and B cell leukemias and lymphomas. In the present study we investigated sCD95 in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. A total of 72 patients was studied (29 AML, 17 MDS, 20 CML and six other myeloproliferative disorders). In AML with active disease, the levels of sCD95 tended to be elevated, but did not correlate with defined clinical or laboratory parameters. In the other disorders, the levels of sCD95 were not generally increased, although some patients had elevated levels. These data strongly suggest that sCD95 in AML patients is not derived from leukemic cells, but is possibly secreted or shed from reactive or stromal cells. This hypothesis is also supported by a group of eight patients with septicemia but not leukemia who had elevated sCD95 (P < 0.05). Furthermore, all three patients with elevated sCD95 who had undergone chemotherapy for AML had major infections. Taken together, this study shows that measuring soluble Fas-receptor in myeloid leukemia is not diagnostically useful, but increased sCD95 may be associated with clinical complications like septicemias.
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PMID:Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. 875 76

Sixteen patients with relapse after allogeneic BMT were treated with donor leukocyte infusions (DLI) from the original donor. The diagnoses at relapse were: CML in chronic phase (CP) (two patients), CML in accelerated phase (AP) (four patients), AML (four patients), MDS (one patient), ALL (four patients) and relapse of Hodgkin's disease (one patient). The patients received a mean of 5.2 x 10(8) leukocytes/kg with a range of 1.4-12.3 x 10(8) leukocytes/kg. Six patients obtained complete remission (CR), one with CML in CP, three with CML in AP, one MDS and one ALL. Partial remission (PR) was seen in three patients, one patient with CML in AP, one with AML and one with Hodgkin's disease. Seven patients had no response (NR) to the infusions, including one patient with CML in CP transplanted with a syngeneic donor. Four patients developed marrow hypoplasia after DLI (three CR and one PR) and two patients (ALL with CR and MDS with CR) were hypoplastic at relapse and marrow hypoplasia continued after DLI. GVHD occurred without GVL, but GVL only occurred in one patient with absence of GVHD. Eleven patients died of leukemia, six patients are alive. Three patients with CML are in CR 12, 12 and 32 months after DLI and one patient with ALL is in CR 15 months after DLI.
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PMID:Treatment of relapse after allogeneic BMT with donor leukocyte infusions in 16 patients. 886 54

Primary myelodysplasia (MDP) and acute and chronic myelogenous leukemias (AML, CML) are considered disorders of clonal stem cell division. Several constitutive gene defects that contribute to the development of abnormal cell behavior have been identified in the hematopoietic cells. The role of bone marrow stroma cells in leukemogenesis, however, has not been established. We studied the organization of the bone marrow (BM) microenvironment to see if it was impaired during the initiation and progression of these malignancies. The buffy coat, hematon, and plasma fractions were separated from BM aspirates taken from healthy donors and diseased subjects at distinct clinical stages. The structural integrity of the BM microenvironment was evaluated analyzing the morphogenetic unit, the hematon. The hematon is a multicellular complex that includes fibroblasts, adipocytes, endothelial cells, resident macrophages, hematopoietic cobblestone area-forming cells (CAFC), high-proliferative potential colony-forming cells (HPP-CFC), granulocyte-macrophage colony-forming unit (GM-CFU), burst-forming unit erythroid (BFU-E), and terminally differentiated cells in normal BM. Hematon complexes were present in most BM aspirates from healthy donors (46H+/55). But they were absent from most of the patients with MDP (21H+/62) and AML (5H+/24) in the first perceptible phase, and from those with CML throughout the disease (5H+/55). Hematon complexes were present in the BM aspirate in 22/36 AML patients at clinical remission after chemotherapy or differentiation therapy. The hematon fraction isolated from normal BM, contained 25 times more 25-hydroxyvitamin D3 and about 500-fold more 1alpha,25-dihydroxyvitamin D3 than the BM plasma. The concentration of 1alpha,25-dihydroxyvitamin D3 was low or undetectable in the BM plasma of some, but not all, patients with MDP (18/35) or AML (9/24). Thus, in the BM microenvironment, the metabolism of low-density lipids and lipophylic hormones are severely impaired prior to initiation or during the accelerated expansion of leukemia cells. The lack of organized stromal network and the decreased level of some lipophylic hormones, acting probably as morphogens, may contribute to the onset and progression of human myeloid leukemias.
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PMID:Bone marrow stromal cell defects and 1 alpha,25-dihydroxyvitamin D3 deficiency underlying human myeloid leukemias. 890 1

This report suggests modest changes in the criteria used for the diagnosis of ET and allows tentative recommendations concerning therapy. As outlined in Table I, we believe that absent stainable marrow iron does not necessarily indicate iron deficiency in these patients and that the serum ferritin and RBC mean corpuscular volume should be incorporated in this assessment. Normal values speak strongly against iron-deficient erythropoiesis. A search for the bcr/abl gene rearrangement should be included with the marrow karyotype to exclude CML. Finally, cytogenetic data and morphologic study of the marrow should be used to be certain that a MDS should not be considered. It may be that measurements of serum thrombopoietin levels may be useful in the future. Nonetheless, in principle, ET remains a diagnosis of exclusion as we have originally suggested. For therapy, HU remains an excellent choice for the older patient at risk for thrombosis. Nonetheless, no myelosuppressive therapy remains a perfectly viable option, particularly for the young patient and the older with low thrombotic risk. The roles of anagrelide and alpha interferon in this setting have not been fully defined. Experience with both has still been relatively short. It would be ideal if prospective, randomized trials could be mounted to address these questions. We conclude with confidence that return to older approaches such as 32P and AA in patients who fail on HU is to be discouraged. The use of anagrelide or interferon alfa seems to be a much more appropriate approach. We have not investigated the role of antithrombotic agents such as aspirin in ET. In PV, the combination of aspirin, 300 mg three times daily, and dipyridamole, 75 mg three times daily, failed to reduce the rate of thrombosis and was associated with an increased rate of hemorrhage. It is rational to suggest that lower doses of aspirin (ie, < 325 mg daily) might be associated with less hemorrhage and, perhaps, a beneficial effect on thrombosis. This remains to be shown.
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PMID:Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. 902 60

To assess the consequence of second BMT (BMT2) for leukemia relapse after allogeneic BMT, we analyzed the clinical course of 66 recipients who were treated by BMT2 in Japan. Diagnoses included 29 ANLL, 27 ALL, six CML and four MDS. Durations between the first BMT (BMT1) to relapse and BMT1 to BMT2 were 13.5 +/- 13.7 months and 17.4 +/- 13.9 months, respectively. Donors for BMT2 were replaced in 11 cases. Thirty-one patients were in CR (or CP) at BMT2. Earlier deaths were observed in those who received BMT2 within 12 months after BMT1, mostly caused by regimen-related toxicity and infections. Overall leukemia-free survival rate was 28% at 2 years and 16% at 4 years. Factors influencing the poor prognosis after BMT2 were early (<6 months) relapse, early (<12 months) BMT2, not in remission at BMT2, and ALL. Intensified conditioning did not affect either remission duration or LFS. Among the 39 cases observed for more than 100 days, 18 developed chronic GVHD (cGVHD) and showed longer remission duration than those without cGVHD. Our analysis indicates that BMT2 as treatment for leukemia relapse is effective in selected cases, and exploration of pre-BMT treatment and post-BMT immunotherapy is warranted.
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PMID:Second allogeneic bone marrow transplantation for post-transplant leukemia relapse: results of a survey of 66 cases in 24 Japanese institutes. 905 12


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