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)

By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.
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PMID:Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders. 348 37

Stem cell factor (SCF), the ligand of the c-kit receptor, is a potent enhancing cytokine for haematopoietic cells in the presence of IL-3, GM-CSF and erythropoietin (Epo). In the clonogenic assays of 63 MDS patients, the addition of rh-SCF + GM-CSF and/or IL-3 induced a significant increase (p < 0.001) in the number and size of CFU-GM. Never reaching the levels of controls, this increase was seen in all FAB subtypes, but particularly in RA. There was no significant increase in cluster formation, even in RAEB or RAEBt. Rh-SCF (10 ng/ml) led to mean increases of up to 26 times in the number of Epo-dependent BFU-E colonies, particularly in RA (p < 0.001) and RAEB (p < 0.05). Individual responses varied widely (especially in RA) from no response to supranormal levels. Added to the weekly refeed of 37 MDS LTBMC, SCF (10 ng/ml) induced only a 7% mean increase in both cell output and the number of clonogenic cells recovered in the supernatant. Immunohistochemical examination of the supernatant showed significant increases in differentiating myeloid cells in all examined cases, and in erythroid cells in 3 cases; blast cells increased in only 3 cases. These data suggest that rh-SCF is capable of at least partially reversing defective MDS myeloid haematopoiesis, and leads no overt risk of leukaemic transformation. Its potent effect on erythroid cells is encouraging for future clinical applications in patients, particularly if they are selected by means of in vitro tests.
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PMID:Effects of recombinant human stem cell factor (rh-SCF) on colony formation and long-term bone marrow cultures (LTBMC) in patients with myelodysplastic syndromes. 750 65

In vitro studies may serve as a guide to clinical strategies with cytokines. In this study, marrows from 26 patients with myelodysplastic syndrome (MDS) were assayed for myeloid progenitor cells in agar gel. Colony stimulating activity was provided by the recombinant human colony stimulating factors granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 3 (IL-3), fusion protein (FP), c-kit ligand (KL) or GM-CSF combined with other cytokines (KL, IL-3). Decreased colony forming units granulocyte-macrophage (CFU-GM) were detected in most cases (69%) compared with normal controls. Neither FP nor the combination of GM-CSF + IL-3 produced more colonies than GM-CSF alone. The number of CFU-GM did not correlate with French American British (FAB) class. All marrows (7) from patients with 5q- showed augmentation of GM-CSF induced colonies with the addition of KL. In contrast, KL augmentation was noted in only 42% of other MDS marrows (p = 0.01). This in vitro result suggests that 5q- may predict a group of MDS patients with a likelihood to respond to the combination of GM-CSF + KL.
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PMID:c-kit ligand augments granulocyte-macrophage colony growth from patients with 5q- syndrome. 750 25

In vitro growth of primitive hematopoietic progenitors is severely impaired in the myelodysplastic syndromes (MDS). To determine if the c-kit ligand mast cell growth factor (MGF) can improve progenitor growth in MDS, we evaluated in vitro responsiveness of bone marrow progenitors from 25 patients to MGF and/or GM-CSF, interleukin-3 (IL-3) and PIXY 321, and examined the relationship between progenitor response and cellular expression of the c-kit receptor. MGF and erythropoietin gave rise to macroscopic colonies and dose-dependently increased CFU-GEMM and BFU-E up to 27-fold in 15 (60%) and 20 (80%) patients, respectively. Among 17 patients with absent growth in lymphocyte-conditioned media, MGF stimulated CFU-GEMM recovery in 59%, compared to 23% with PIXY 321, 12% with IL-3 and 8% with GM-CSF. Cytokine combinations did not augment recovery of erythropoietin-dependent progenitors above that achieved with MGF alone. MGF and/or IL-3 were comparatively weak stimulants of CFU-GM formation, whereas GM-CSF and PIXY in combination with MGF increased colony number 2- to 15-fold in 60 and 70% of patients, respectively, while preserving maturation competence as evidenced by colony composition and increased colony/cluster ratio. The stimulatory effects of MGF were observed in all morphologic categories of MDS except chronic myelomonocytic leukemia. A mononuclear cell population expressing the c-kit receptor was identified by flow cytometry in 57% of cases. Neither SR-1 reactivity nor cytogenetic pattern predicted progenitor response to MGF. These data indicate that MGF improves the colony-forming capacity of hematopoietic progenitors in MDS and is a potent co-stimulant of multipotent and committed progenitor recovery. The heterogeneity in MGF responsiveness implies an intrinsic defect in growth regulation not explained by cellular loss of c-kit display.
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PMID:Mast cell growth factor (c-kit ligand) restores growth of multipotent progenitors in myelodysplastic syndrome. 751 48

To evaluate the effects of colony-stimulating factors (CSFs) on pathological cells from myelodysplastic syndromes (MDS), the blast cells from 19 MDS patients (eight low-risk MDS, six high-risk MDS, and five leukemic transformation of MDS [LT-MDS]) and four normal volunteers were successfully enriched by separating CD34-positive cells by the use of immunomagnetic beads, and their responsiveness to granulocyte or granulocyte-macrophage CSF (G-CSF or GM-CSF) was examined in short-term liquid suspension culture. The proliferation of MDS blast cells was clearly promoted by these CSFs in all cases examined, but considerable percentages of them often remained immature compared with the favorable maturation of normal blast cells, especially in the more advanced disease groups (LT-MDS and high-risk MDS) that included two prominent cases with a remarkable blast cell growth without maturation induction by CSFs. The expression of esterase activities was rather sluggish in the MDS cases, in contrast to normal expression. These data showed that MDS blast cells proliferate in response to CSFs but that maturation is less than that observed with normal blast cells in vitro. Much care should be taken with in vivo application of CSFs to high-risk MDS patients.
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PMID:Altered responses of purified blast cells from the myelodysplastic syndromes to colony-stimulating factors in vitro: comparison with normal blast cells. 751 87

Administration of G- and GM-CSF increases the neutrophil counts in a number of clinical situations. GM-CSF shows the additional effect of increasing the number of monocytes and eosinophil granulocytes. Both G- and GM-CSF affect of neutrophil functions, in the case of GM-CSF there are some potentially negative effects on neutrophil migration and adhesiveness. The clinical relevance of the various effects on mature haematopoietic cells is not fully understood. Clinical data with G-CSF treatment indicate that increased levels of neutrophil granulocytes following cytotoxic chemotherapy may translate into clinical benefit such as a decreased rate of neutropenic infection and an increased cytotoxic chemotherapy dose even though the data are conflicting and the risk of "laboratory cosmetics" is apparent. Regarding treatment with GM-CSF following chemotherapy, the clinical benefit is unclear. The clinical benefit of GM-CSF-induced monocytes and eosinophils is unknown. G- and GM-CSF accelerates neutrophil recovery following autologous or allogeneic BMT. The influence on neutropenic infections is, however, less impressive. Pretreatment with G- or GM-CSF increases the yield of peripheral stem cell harvest, thereby reducing the number of leukaphereses needed. Transplantation of G- and GM-CSF primed autologous peripheral stem cells tends to reduce the period of post-transplant cytopenia, particularly thrombocytopenia, in comparison with traditional ABMT. In patients with MDS, G- and GM-CSF appear to increase the number of neutrophil granulocytes and there is some evidence that patients with severe infectious problems will benefit from this treatment. However, little influence was seen on the main clinical problems with these patients, which are anaemia and thrombocytopenia. In conclusion, G- and GM-CSF are two different proteins with different properties in vivo and in vitro. GM-CSF has, compared with G-CSF, more complex pharmacological effects and a more trouble-some side-effect profile. Early clinical development indicates that both compounds have a substantial influence on the levels of certain blood cells. Whether the increases in different blood cells translate into long-term clinical benefit for greater patient groups is the focus of ongoing research. The effects of G- and GM-CSF may be potentiated by other cytokines, an area which is presently being explored.
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PMID:G- and GM-CSF in oncology and oncological haematology. 751 79

To investigate the role of colony stimulating factors (CSFs) in the proliferation and differentiation of progenitor cells from myelodysplastic syndromes (MDS), marrow progenitor cells from 18 MDS patients were highly purified using CD34 monoclonal antibody and immunomagnetic microspheres (MDS CD34+ cells). These cells were cultured in serum-free medium with various combinations of five colony stimulating factors (CSFs): recombinant human interleukin-3 (rIL-3), granulocyte/macrophage-CSF (rGM-CSF), granulocyte-CSF (rG-CSF), macrophage-CSF (rM-CSF), and erythropoietin (rEP). Among the tested CSFs, such as rM-CSF, rG-CSF, rGM-CSF and rIL-3, a combination of the first three CSFs was the most effective stimulus for the proliferation of non-erythroid MDS progenitor cells. An increase of undifferentiated "blast" cell colonies in 5/18 MDS patients occurred and these 5 patients belonged to the high-risk group. In the presence of these three CSFs, rIL-3 had no effect on the proliferation and differentiation of MDS CD34+ cells; however, IL-3 was efficient for the proliferation of MDS CD34+ cells to the erythroid lineage. rGM-CSF or rIL-3 alone did not efficiently support proliferation and differentiation of CD34+ cells. M-CSF is present in normal human serum at a concentration of 550 +/- 110 U/ml, a concentration exceeding that used in this study (100 U/ml). Therefore, in vivo administration of G-CSF combined with GM-CSF to MDS patients may be one of the most effective CSF combinations for proliferation of MDS progenitor cells to the non-erythroid lineage. However, the effect on the capacity for differentiation was minimal, especially in patients belonging to the high-risk group.
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PMID:Proliferation and differentiation of myelodysplastic CD34+ cells in serum-free medium: II. Response to combined colony-stimulating factors. 753 45

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
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PMID:Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation. 754 18

The ability of induction of differentiation of leukemia cells was first proved by cultured leukemia cells, and such ability has been also confirmed clinically as a result of observation of the dramatic effect of all-trans retinoic acid on acute promyelocytic leukemia and the usefulness of low-dose of ara-C therapy for acute myeloid leukemia. We studied differentiation induction of primary cultured bone marrow cells from myelodysplastic syndrome (MDS) patients by ara-C and VP16 with or without addition of G-CSF. We also studied clinical efficacy of differentiation therapy in 56 patients with MDS. Differentiation induction effects were observed in 3 of 14 patients treated with G-CSF in combination with low-dose of ara-C or low-dose of VP16. In addition, high-dose methylprednisolone therapy, GM-CSF and anabolic steroid therapy also showed similar effect on refractory anemia, even in a few patients. Since these results suggested the usefulness of differentiation therapy of MDS, it is earnestly hoped that more effective therapy, including a concomitant use of cytokine, might be established as soon as possible.
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PMID:[Differentiation therapy for myelodysplastic syndrome]. 768 64

Standard intensive induction therapy is tolerated poorly by elderly patients with acute myeloblastic leukemia (AML). We treated 19 elderly patients with AML, including seven with a prior myelodysplastic syndrome (MDS) with a combination of low dose cytarabine, hydroxyurea, and GM-CSF. The percentage of blasts in S-phase was evaluated prior to and 24 hr after starting the GM-CSF infusion. Cell cycle analysis was performed by flow cytometry using propidium iodine staining with fluorescein isothiocyanate-conjugated monoclonal antibody to the myeloid antigen CD 33. Seven out of nineteen (37%) achieved a complete remission (CR) and six (31%) a partial remission (PR) for an overall response rate of 68% (13/19). There were three early deaths from infectious complications or organ failure. One patient died from disseminated fungal infection after attaining a PR. The medial overall survival was 9.5 months with a range of 1 to 23+ months. The projected median survival for the patients with de novo AML is greater than 23 months. The percentage of CD 33+ cells in S-phase increased from a mean of 11.6+/-2.7 (SEM) pre GM-CSF to 19.0+/-3.7 (SEM) post GM-CSF (P < 0.001). Patients with prior MDS demonstrated a greater increment (post-pre) in S-phase activity after GM-CSF administration (P = 0.02). There was a correlation between the increase in percent of CD 33+ cells in S-phase and the degree of cytoreduction as determined by the day 14 bone marrow biopsy (r = .78). The toxicity of the regimen was limited to the hematopoietic system. Sixteen out of nineteen patients (84%) and 12/13 (92%) of the responding patients had bone marrow aplasia on day 14. No patients experienced > grade 2 gastrointestinal toxicity. There was no neurologic or cardiac toxicity. These data suggest that the combination of hydroxyurea, GM-CSF, and cytarabine is an effective remission-induction regimen in elderly patients with AML.
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PMID:Granulocyte-macrophage colony stimulating factor (GM-CSF) priming in the treatment of elderly patients with acute myelogenous leukemia. 774 Nov 38


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