Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify some characteristics of phosphatidylinositol glycan-class A gene (PIG-A) mutations in aplastic anemia (AA) and myelodysplastic syndrome (MDS) patients compared with those in paroxysmal nocturnal hemoglobinuria (PNH) patients, we investigated PIG-A mutations in CD59- granulocytes and CD48- monocytes from seven AA, eight MDS, and 11 PNH Japanese patients. The most frequent base or type abnormalities of the PIG-A gene in AA and MDS patients were base substitutions or missense mutations, respectively, and deletions or frameshift mutations, respectively, in PNH patients. Several PIG-A mutations, most of which were statistically minor, were found in glycosylphosphatidylinositol-negative cells from all AA and MDS patients but not from all PNH patients. However, the common PIG-A mutations during the clinical course between CD59- granulocytes and/or CD48- monocytes from each AA or MDS patient, except for Case 5, were not found. PIG-A mutations were different between the granulocytes and monocytes from five AA and five MDS patients. Our results indicate that there were some characteristics of PIG-A mutations in AA and MDS patients compared with PNH patients and that several minor PNH clones in these patients occurred at random during the clinical course. This partly explains the transformation of AA or MDS to PNH at intervals.
Leukemia 2006 Apr
PMID:High frequency of several PIG-A mutations in patients with aplastic anemia and myelodysplastic syndrome. 1646 65

Carcinogenesis, at least for some types of cancer, can be interpreted as the consequence of selection of mutated cells similar to what, in the theory of evolution, occurs at the population level. Instead of considering a population of organisms, we can refer to a population of cells belonging to multicellular organisms. Many carcinogens are mutagens, and the observed geographic distribution of cancer is, at least in part, attributable to environmental mutagens. However, the rapid change in risk for some cancers after migration suggests that carcinogenesis involves--in addition to mutations--some late event that most probably consists of the selection of cells already carrying mutations. We review a few examples of such selective pressures: finasteride in prostate cancer, vitamin supplementation in smokers, acquired resistance to chemotherapy, peripheral resistance to insulin, and sunlight and mutations in melanoma. A disease model for such a hypothesis is represented by Paroxysmal Nocturnal Hemoglobinuria (PNH). Mutations can be present at birth, as in the case of PNH, and can have a frequency much higher than the occurrence of the corresponding disease (PNH or lymphocytic leukaemia in children). However, PNH does not require a mutator phenotype, only a mutant phenotype followed by selection. A characteristic feature of cancer, instead, is likely to be the development of the mutator phenotype. We propose a 'Darwinian' model of carcinogenesis. If the model is correct, it suggests that prevention is more complex than avoiding exposure to mutagens. Mutations and genetic instability can be already present at birth. Mutations can be selected in the course of life if they increase survival advantage of the cell under certain environmental circumstances. In addition, gene-environment interactions cannot be interpreted according to a simplified linear model (based on the 'analysis of variance' concept); experimental work suggests that a more comprehensive non-linear interpretation based on the idea of 'norm of reaction' is needed.
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PMID:The population dynamics of cancer: a Darwinian perspective. 1699 Feb 87

Human leukocyte antigen (HLA) DR15 is associated with autoimmune cytopenia in patients with aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Presence of this antigen also predicts response to immunosuppressive treatment. If DR15 expression on hematopoietic cells also favors induction of immune responses in an allogeneic setting, a lower relapse rate after hematopoietic stem cell transplantation (HSCT) might result through an enhanced graft-versus-leukemia effect. We retrospectively analyzed outcome of HLA-identical sibling HSCT in 192 consecutive patients with acute or chronic leukemia or non-Hodgkin lymphoma. Patients carrying the DR15 antigen had a higher estimated 5-year overall survival (76%) than did DR15-negative patients (55%; P = .04). Improved survival for DR15 patients was due to a significant decrease in death from relapse (5% for DR15(+) versus 24% for DR15(-); P = .02), whereas no difference was seen for rates of transplant-related mortality (19% and 21%, respectively; P = .76). Findings were confirmed by multivariate analyses. Our results show an association of DR15 with a decreased risk of disease relapse and improved survival after HSCT for leukemia or non-Hodgkin lymphoma. This adds to the growing list of links between DR15 and immune reactions in hematopoiesis.
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PMID:Human leukocyte antigen DR15 is associated with reduced relapse rate and improved survival after human leukocyte antigen-identical sibling hematopoietic stem cell transplantation. 1738 56

To identify novel autoantibodies in acquired aplastic anemia (AA), we screened the sera of patients with AA possessing small populations of paroxysmal nocturnal hemoglobinuria (PNH)-type cells for the presence of antibodies (Abs) which recognize proteins derived from a leukemia cell line, UT-7. Immunoblotting using proteins derived from lysates or culture supernatants of UT-7 cells revealed the presence of IgG Abs specific to an 80-kDa protein. Peptide mass fingerprinting identified this 80-kDa protein as moesin. Enzyme-linked immunosorbent assay (ELISA) using recombinant moesin showed high titers of antimoesin Abs in 25 (37%) of 67 patients with AA. Moesin was secreted from several myeloid leukemia cell lines other than UT-7, such as OUN-1 and K562, as an exosomal protein. The presence of antimoesin Abs was significantly correlated with the presence of PNH-type cells and antidiazepam-binding inhibitor-related protein-1 (DRS-1) Abs. Patients with AA that did not show any of these 3 markers tended to respond poorly to immunosuppressive therapy. These findings suggest that a B-cell response to moesin, possibly derived from hematopoietic cells, frequently occurs in patients with AA and that detection of antimoesin Abs in combination with other markers may be useful in diagnosing immune pathophysiology in patients with AA.
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PMID:Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia. 1711 Apr 58

The unique structure of the T cell receptor (TCR) enables molecular identification of individual T cell clones and provides an unique opportunity for the design of molecular diagnostic tests based on the structure of the rearranged TCR chain e.g., using the TCR CDR3 region. Initially, clonal T cell malignancies, including T cell large granular lymphocyte leukemia (T-LGL), mucosis fungoides and peripheral T cell lymphoma were targets for the TCR-based analytic assays such as detection of clonality by T-gamma rearrangement using y-chain-specific PCR or Southern Blotting. Study of these disorders facilitated further analytic concepts and application of rational methods of TCR analysis to investigations of polyclonal T cell-mediated diseases. In hematology, such conditions include graft versus host disease (GvHD) and immune-mediated bone marrow failure syndromes. In aplastic anemia (AA), myelodysplastic syndrome (MDS) or paroxysmal nocturnal hemoglobinuria (PNH), cytotoxic T cell responses may be directed against certain antigens located on stem or more lineage-restricted progenitor cells in single lineage cytopenias. The nature of the antigenic targets driving polyclonal CTL responses remains unclear. Novel methods of TCR repertoire analysis, include VB flow cytometry, peptide-specific tetramer staining, in vitro stimulation assays and TCR CDR3-specific PCR. Such PCR assay can be either VB family-specific or multiplexed for all VB families. Amplified products can be characterized and quantitated to facilitate detection of the most immunodominant clonotypes. Such clonotypes may serve as markers for the global polyclonal T cell response. Identification of these clonotypes can be performed in blood and tissue biopsy material by various methods. Once immunodominant clonotypes corresponding to pathogenic CTL clones are identified they can serve as surrogate markers for the activity of the pathophysiologic process or even indicate the presence of specific antigens. The relevance of the individual clonotypes can be ascertained from clinical correlations with the activity of the disease. Quantitative clonotypic assays such as sequencing of multiple CDR3 clones or clonotypic Taqman PCR can be applied for the monitoring of the immunosuppressive therapy and prediction of relapse. Future technologies may allow for the design of clonotypic microarrays or other more clinically applicable methods of clonotypic diagnostics. Similarly, identification of immunodominant clonotypes may facilitate targeting of autoimmune or malignant clones with vaccination and induction of anti-idiotypic responses.
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PMID:Immune-mediated bone marrow failure syndromes of progenitor and stem cells: molecular analysis of cytotoxic T cell clones. 1737 39

Clonal hematopoiesis, observed in certain forms of marrow failure including aplastic anemia (AA), may be due to stem cell depletion. Alternatively, oligoclonality may be a result of recruitment of a preexisting defective clone, such as in paroxysmal nocturnal hemoglobinuria (PNH) or myelodysplastic syndromes (MDS). In PNH, exogenous permissive factors may be required for dominance of the abnormal clone, while in MDS, stem cells undergo transformation steps leading to a growth advantage. Stem or multipotent progenitor cell involvement in PNH is evidenced by long-term persistence of a clonal defect and its presence in all blood cells. In MDS, some clonal aberrations may have a 'founder-effect' and additional defects are secondary. Metaphase cytogenetics measures the proportion of clonal cells within dividing progenitor but not mature cells. Owing to low resolution, lesions can be found in only approximately 50% of MDS patients. This shortcoming may be overcome by application of newer technologies such as comparative genomic hybridization and SNP array-based karyotyping (SNP-A). SNP-A facilitates identification of cryptic lesions in bone marrow failure patients with normal or abnormal cytogenetics and allows for detection of loss of heterozygosity as a result of uniparental disomy, a lesion frequently found in MDS.
Leukemia 2007 Aug
PMID:Clonality of the stem cell compartment during evolution of myelodysplastic syndromes and other bone marrow failure syndromes. 1755 86

Patients with bone marrow failure syndromes are at risk for the development of clonal neoplasms, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia (MDS), and acute myelogenous leukemia (AML). Approximately 10% to 20% of those who survive acquired aplastic anemia will develop a clonal disease within the decade following their diagnosis. The relative risk of clonal neoplasms is very significantly increased in children and adults with inherited bone marrow failure syndromes as well. Until recently, the mechanisms underlying clonal evolution have been opaque, but a sufficient amount of evidence has now accumulated to support a model in which cells resistant to extracellular apoptotic cues are selected from the stem cell pool. Indeed, in the past two years this paradigm has been validated in preclinical models that are robust enough to reconsider new therapeutic objectives in aplastic states and to support the planning and development of rationally designed leukemia prevention trials.
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PMID:Bone marrow failure as a risk factor for clonal evolution: prospects for leukemia prevention. 1802 7

THE HEMOLYTIC ANEMIAS OF UNKNOWN CAUSE CAN BE SEPARATED INTO TWO MAIN GROUPS: (1) those produced by a defect in cell structure, which is usually hereditary, and (2) those due to a hemolysin of immune-body type.The hemolytic anemias associated with hypersensitivity to drugs and disease processes such as leukemia are less well understood and need further investigation. Splenectomy is the only effective treatment in congenital hemolytic jaundice and in acquired hemolytic anemia; the operation should be carried out promptly in most cases. Transfusion may be used in all varieties of hemolytic disease and is the only effective form of therapy in sickle-cell anemia and paroxysmal nocturnal hemoglobinuria.
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PMID:Hemolytic anemias recent advances in diagnosis and treatment. 1811 27

Telomeres, consisting of nucleotide repeats and a protein complex at chromosome ends, are essential in maintaining chromosomal integrity. Dyskeratosis congenita (DC) is the inherited bone marrow failure syndrome (IBMFS) that epitomizes the effects of abnormal telomere biology. Patients with DC have extremely short telomere lengths (<1st percentile) and many have mutations in telomere biology genes. Interpretation of telomere length in other IBMFSs is less straightforward. Abnormal telomere shortening has been reported in patients with apparently acquired hematologic disorders, including aplastic anemia, myeolodysplasia, paroxysmal nocturnal hemoglobinuria, and leukemia. In these disorders, the shortest-lived cells have the shortest telomeres, suggestive of increased hematopoietic stress. Telomeres are also markers of replicative and/or oxidative stress in other complex disease pathways, such as inflammation, stress, and carcinogenesis. The spectrum of related disorders caused by mutations in telomere biology genes extends beyond classical DC to include marrow failure that does not respond to immunosuppression, idiopathic pulmonary fibrosis, and possibly other syndromes. We suggest that such patients be categorized as having an inherited disorder of telomere biology. Longitudinal studies of patients with very short telomeres but without classical DC are necessary to further understand the long-term sequelae, such as malignancy, osteonecrosis/osteoporosis, and pulmonary and liver disease.
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PMID:The role of telomere biology in bone marrow failure and other disorders. 1816 98

Hematopoietic stem cells (HSCs) are responsible for the production of mature blood cells in bone marrow; peripheral pancytopenia is a common clinical presentation resulting from several different conditions, including hematological or extra-hematological diseases (mostly cancers) affecting the marrow function, as well as primary failure of hematopoiesis. Primary bone marrow failure syndromes are a heterogeneous group of diseases with specific pathogenic mechanisms, which share a profound impairment of the hematopoietic stem cell pool resulting in global or selective marrow aplasia. Constitutional marrow failure syndromes are conditions caused by intrinsic defects of HSCs; they are due to inherited germline mutations accounting for specific phenotypes, and often involve also organs and systems other than hematopoiesis. By contrast, in acquired marrow failure syndromes hematopoietic stem cells are thought to be intrinsically normal, but subjected to an extrinsic damage affecting their hematopoietic function. Direct toxicity by chemicals or radiation, as well as association with viruses and other infectious agents, can be sometimes demonstrated. In idiopathic Aplastic Anemia (AA) immunological mechanisms play a pivotal role in damaging the hematopoietic compartment, resulting in a depletion of the hematopoietic stem cell pool. Clinical and experimental evidences support the presence of a T cell-mediated immune attack, as confirmed by clonally expanded lymphocytes, even if the target antigens are still undefined. However, this simple model has to be integrated with recent data showing that, even in presence of an extrinsic damage, preexisting mutations or polymorphisms of genes may constitute a genetic propensity to develop marrow failure. Other recent data suggest that similar antigen-driven immune mechanisms may be involved in marrow failure associated with lymphoproliferative or autoimmune disorders characterized by clonal expansion of T lymphocytes, such as Large Granular Lymphocyte leukemia. In this wide spectrum, a unique and intriguing condition is Paroxysmal Nocturnal Hemoglobinuria (PNH); even in presence of a somatic mutation of the PIG-A gene carried by one or more HSCs and their progeny, the typical marrow failure in PNH is likely due to pathogenic mechanisms similar to those involved in AA, and not to the intrinsic abnormality conferred to the clonal population by the PIG-A mutation. The study of hematopoietic stem cell function in marrow failure syndromes provides hints for specific molecular pathways disturbed in many diseases of hematopoietic and non-hematopoietic stem cells. Beyond the specific interest of investigators involved in the field of these rare diseases, marrow failure syndromes represent a model that provides intriguing insight into quantity and function of normal hematopoietic stem cells, improving our knowledge on stem cell biology.
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PMID:Function and malfunction of hematopoietic stem cells in primary bone marrow failure syndromes. 1822 Aug 91


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