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)

Stem cell transplantations were performed in 69 children at Siriraj Hospital over a ten year period. The source of stem cells was bone marrow (60), peripheral blood (3), or cord blood (6). The diseases treated included 35 thalassemias, 11 Burkitt's lymphoma, five non-Hodgkin's lymphoma, five aplastic anemia, eight acute leukemia, and one each of neuroblastoma, severe combined immunodeficiency, Wiskott-Aldrich syndrome, myelodysplastic syndrome, and pyruvate kinase deficiency. The success rate of stem cell transplantation in Thai children varied according to the underlying diseases of the patients, ranging from 50% in acute leukemia to 100% in aplastic anemia. The outcome of stem cell transplantation in 35 thalassemic children revealed 23 (79.4%) were cured, whereas three (10.3%) remain alive with disease and the other three (10.3%) died. The incidence of graft-versus-host disease was low hen compared with that of Western countries. It is concluded that bone marrow, peripheral blood and cord blood stem cell transplantation will be the treatment of choice and will be widely used in the future to cure many hematologic and malignant disorders in children.
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PMID:Bone marrow, peripheral blood and cord blood stem cell transplantation in children: ten years' experience at Siriraj Hospital. 988 40

Between October 1995 and October 1998, 24 children aged 9 months to 17 years (median 11 years) underwent cytokine-mobilized allogeneic peripheral blood stem cell (PBSC) transplantation for treatment of hematological disorders. All of the transplants were the first allogeneic transplant for the recipient. Twenty patients were transplanted for hematological malignancies (ALL = 8, AML = 6, CML = 4, MDS = 2) and four patients were transplanted for non-malignant disease (thalassemia major = 2, Wiskott-Aldrich syndrome = 1, Kostmann's syndrome = 1). Nineteen donors were HLA-identical siblings, four were HLA-matched or single antigen mismatched parents, and one was a syngeneic transplant. Donors aged 8 to 38 years (median 15 years, 14 donors <18 years) received G-CSF 10 microg/kg/day subcutaneously beginning 4 days before PBSC collection and were submitted to one to three leukapheresis collections. The median CD34+ cell yield was 7.8 x 106 cells/kg recipient body weight. All patients achieved an ANC >0.5 x 109/l after a median of 13 days (range 10-21). Twenty-three patients eventually achieved platelet transfusion independence. One patient died on day 63 without ever achieving platelet transfusion independence. Four patients received platelet transfusions to maintain a platelet count well above 20 x 109/l due to bleeding complications. Of the 19 evaluable patients, the median time to a non-transfused platelet count of 20 x 109/l was 12 days (range 0-44). Ten of 23 at-risk patients developed acute GVHD grades II to IV, with grades III to IV in four patients. Twelve of 19 patients followed for at least 100 days have developed chronic GVHD (extensive = 2, limited = 10) with an actuarial risk of chronic GVHD of 75% at 1 year. The Kaplan-Meier estimate of event-free survival is 65% at 2 years. Four patients died (GVHD = 3, VOD = 1), three patients relapsed, and one patient with thalassemia major had a late graft failure with autologous recovery. Based upon our experience, allogeneic PBSCT is safe for both pediatric donors and recipients and engraftment of neutrophils and platelets is rapid. Bone Marrow Transplantation (2000) 25, 13-18.
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PMID:Cytokine-mobilized allogeneic peripheral blood stem cell transplants in children result in rapid engraftment and a high incidence of chronic GVHD. 1065 8

Two forms of inherited deficiency of neutrophil numbers are cyclic hematopoiesis and severe congenital neutropenia. In cyclic hematopoiesis, neutrophil counts oscillate opposite monocytes in a 3-week cycle. Severe congenital neutropenia consists of static neutropenia and a predisposition to myelodysplasia and acute myelogenous leukemia. All cases of cyclic neutropenia and most cases of severe congenital neutropenia result from heterozygous germline mutations in the gene encoding neutrophil elastase, ela2. Recent work extends the list of neutropenia genes to include WASp, Gfi-1, adaptin, and tafazzin. Studies of mosaic patients suggest that ela2 mutations act in a cell-autonomous fashion. A hypothetical feedback circuit potentially interconnects these genes. Genetic dissection of signaling in model organisms along with experimental hematology implicate C/EPBepsilon, RUNX1/AML1, Notch family members, LEF1, and Cdc42 as additional nodes in this pathway. The authors propose that neutrophil elastase acts as an inhibitor of myelopoiesis, substantiating a chalone hypothesis proposed many years ago.
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PMID:Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic revival of the chalone hypothesis. 1248 11

There have been many recent advances in our understanding of the molecular basis of neutropenia disorders, primarily through advances in genetic analysis of inherited disorders. Molecular and cellular studies now suggest that accelerated apoptosis of neutrophil precursors in the bone marrow is the common pathophysiologic mechanism. Severe congenital neutropenia and cyclic neutropenia, both usually inherited as autosomal-dominant disorders, are caused by mutations in the neutrophil elastase gene. Myelokathexis is attributed to the downregulation of the bcl-x protein, but the genetic basis is not yet known. The genes for several diseases with more complex phenotypes (eg, glycogen storage disease type 1b, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, dyskeratosis congenita, Griscelli syndrome, Barth syndrome, and Wiskott-Aldrich syndrome) have all been identified recently. The molecular mechanisms for most acquired disorders causing neutropenia (eg, idiopathic neutropenia, pure white-cell aplasia, myelodysplasia, and aplastic anemia) are not yet known. Granulocyte colony stimulating factor (G-CSF) is effective treatment for several of these conditions. Through better understanding of these disorders, we anticipate that better treatments will be found in the future.
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PMID:Molecular basis and therapy of disorders associated with chronic neutropenia. 1290 73

Tacrolimus (FK506)/mycophenolate mofetil (MMF) has been demonstrated to be an effective salvage therapy for steroid-resistant chronic graft-versus-host disease (GVHD), but its effectiveness as prophylaxis for acute GVHD (aGVHD) is unknown. We investigated the safety and efficacy of FK506/MMF in preventing aGVHD and sparing the use of methotrexate and methylprednisolone in childhood and adolescent allogeneic stem cell transplant (AlloSCT) recipients. Thirty-four childhood and adolescent patients (median age, 7 years; range, 0.5-21 years; 24 males and 10 females) undergoing 37 AlloSCTs for malignant (n = 22) and nonmalignant (n = 12) disorders received FK506 (0.03 mg/kg/d by continuous intravenous infusion) and MMF (15 mg/kg per dose orally or intravenously twice daily). Stem cell sources included 22 umbilical cord blood donors (21 unrelated and 1 related), 6 related bone marrow donors, and 9 related peripheral blood donors. Malignant diagnoses included 7 acute lymphoblastic leukemias, 3 acute myeloid leukemias, 1 acute promyelocytic leukemia, 2 non-Hodgkin lymphomas, 4 Hodgkin diseases, 3 chronic myeloid leukemias, and 2 neuroblastomas; nonmalignant diagnoses included 2 beta-thalassemias, 1 sickle cell disease, 4 aplastic anemias, 1 Wiskott-Aldrich syndrome, 1 Hurler syndrome, 2 hemophagocytic lymphohistiocytoses, and 1 myelodysplastic syndrome. The probability of developing grade > or =II aGVHD was 45.4% +/- 9.7% (7 related bone marrow/related peripheral blood; 5 umbilical cord blood), and for chronic GVHD it was 38.1% +/- 19.7%. FK506/MMF was well tolerated. Three patients had grade III to IV neurotoxicity (disorientation and leukoencephalopathy); 4 patients developed grade III to IV nephrotoxicity (all received concomitant nephrotoxins). Patients who achieved target mycophenolic acid levels (1.0-3.5 microg/mL) before day +30 had a significantly reduced incidence of developing grade >/=II aGVHD (16.7% +/- 15.2% versus 100%; P <.02). These results suggest that FK506/MMF is well tolerated and may be a safe and effective methotrexate- and methylprednisolone-sparing alternative GVHD prophylaxis regimen after AlloSCT. Further pharmacokinetic and pharmacodynamic studies are ongoing in pediatric and adolescent AlloSCT recipients to define optimal MMF dosing.
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PMID:A pilot study of tacrolimus and mycophenolate mofetil graft-versus-host disease prophylaxis in childhood and adolescent allogeneic stem cell transplant recipients. 1507 23

Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent bacterial infections, and maturation arrest in the bone marrow. Although many cases have mutations in the ELA2 gene encoding neutrophil elastase, a significant proportion remain undefined at a molecular level. A mutation (Leu270Pro) in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) resulting in an X-linked SCN kindred has been reported. We therefore screened the WAS gene in 14 young SCN males with wild-type ELA2 and identified 2 with novel mutations, one who presented with myelodysplasia (Ile294Thr) and the other with classic SCN (Ser270Pro). Both patients had defects of immunologic function including a generalized reduction of lymphoid and natural killer cell numbers, reduced lymphocyte proliferation, and abrogated phagocyte activity. In vitro culture of bone marrow progenitors demonstrated a profound reduction in neutrophil production and increased levels of apoptosis, consistent with an intrinsic disturbance of normal myeloid differentiation as the cause of the neutropenia. Both mutations resulted in increased WASp activity and produced marked abnormalities of cytoskeletal structure and dynamics. Furthermore, these results also suggest a novel cause of myelodysplasia and that male children with myelodysplasia and disturbance of immunologic function should be screened for such mutations.
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PMID:Two novel activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia. 1680 17

X-linked neutropenia (XLN, OMIM #300299) is a rare form of severe congenital neutropenia. It was originally described in a three-generation family with five affected members that had an L270P mutation in the GTP-ase binding domain (GBD) of the Wiskott-Aldrich syndrome protein (WASP) [Devriendt et al (2001) Nature Genetics, Vol. 27, 313-317]. Here, we report and describe a large three-generation family with XLN, with 10 affected males and eight female carriers. A c.882T>C mutation was identified in the WAS gene, resulting in an I294T mutation. The infectious course is variable and mild in view of the profound neutropenia. In addition to the original description, low-normal IgA levels, low to low-normal platelet counts and reduced natural killer (NK)-cell counts also appear as consistent XLN features. However, inverted CD4/CD8 ratios were not found in this family, nor were cases identified with myelodysplastic syndrome or acute myeloid leukaemia. Female carriers exhibited a variable attenuated phenotype. Like L270P WASP, I294T WASP is constitutively active towards actin polymerization. In conclusion, this largest XLN kindred identified to date provides new independent genetic evidence that mutations disrupting the auto-inhibitory GBD of WASP are the cause of XLN. Reduced NK cells, low to low normal platelet counts and low to low-normal IgA levels are also features of XLN.
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PMID:A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene. 1900 68

X-linked neutropenia (XLN) is a rare form of Congenital Neutropenia (CN) caused by inherited gain-of-function mutations of WAS. Here we report 2 cases of the original L270P X-linked neutropenia kindred that evolved to MDS or AML, with acquisition of G-CSFR (CSF3R) mutations and monosomy 7. Thus, leukemic transformation with acquisition of CSF3R mutations and monosomy 7 is not restricted to classical congenital neutropenia with autosomal inheritance, but can also occur in other genotypes of inherited neutropenia.
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PMID:G-CSF receptor (CSF3R) mutations in X-linked neutropenia evolving to acute myeloid leukemia or myelodysplasia. 1979 77

Leukocytes rely on dynamic actin-dependent changes in cell shape to pass through blood vessels, which is fundamental to immune surveillance. Wiskott-Aldrich Syndrome protein (WASp) is a hematopoietic cell-restricted cytoskeletal regulator important for modulating cell shape through Arp2/3-mediated actin polymerization. A recently identified WASp(I294T) mutation was shown to render WASp constitutively active in vivo, causing increased filamentous (F)-actin polymerization, high podosome turnover in macrophages, and myelodysplasia. The aim of this study was to determine the effect of WASp(I294T) expression in lymphocytes. Here, we report that lymphocytes isolated from a patient with WASp(I294T), and in a cellular model of WASp(I294T), displayed abnormal microvillar architecture, associated with an increase in total cellular F-actin. Microvillus function was additionally altered as lymphocytes bearing the WASp(I294T) mutation failed to roll normally on L-selectin ligand under flow. This was not because of defects in L-selectin expression, shedding, cytoskeletal anchorage, or membranal positioning; however, under static conditions of adhesion, WASp(I294T)-expressing lymphocytes exhibited altered dynamic interaction with L-selectin ligand, with a significantly reduced rate of adhesion turnover. Together, our results demonstrate that WASp(I294T) significantly affects lymphocyte membrane topography and L-selectin-dependent adhesion, which may be linked to defective hematopoiesis and leukocyte function in affected patients.
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PMID:A congenital activating mutant of WASp causes altered plasma membrane topography and adhesion under flow in lymphocytes. 2059 19

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and a lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.
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PMID:The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function. 2117 75


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