Abstract:
:Iron is a vitally important element in mammalian metabolism because of its unsurpassed versatility as a biologic catalyst. However, when not appropriately shielded or when present in excess, iron plays a key role in the formation of extremely toxic oxygen radicals, which ultimately cause peroxidative damage to vital cell structures. Organisms are equipped with specific proteins designed for iron acquisition, export, transport, and storage as well as with sophisticated mechanisms that maintain the intracellular labile iron pool at an appropriate level. These systems normally tightly control iron homeostasis but their failure can lead to iron deficiency or iron overload and their clinical consequences. This review describes several rare iron loading conditions caused by genetic defects in some of the proteins involved in iron metabolism. A dramatic decrease in the synthesis of the plasma iron transport protein, transferrin, leads to a massive accumulation of iron in nonhematopoietic tissues but virtually no iron is available for erythropoiesis. Humans and mice with hypotransferrinemia have a remarkably similar phenotype. Homozygous defects in a recently identified gene encoding transferrin receptor 2 lead to iron overload (hemochromatosis type 3) with symptoms similar to those seen in patients with HFE-associated hereditary hemochromatosis (hemochromatosis type 1). Transferrin receptor 2 is primarily expressed in the liver but it is unclear how mutant forms cause iron overload. Mutations in the gene encoding the iron exporter, ferroportin 1, cause iron overload characterized by iron accumulation in macrophages yet normal plasma iron levels. Plasma iron, together with dominant inheritance, discriminates iron overload due to ferroportin mutations (hemochromatosis type 4) from hemochromatosis type 1. Heme oxygenase 1 is essential for the catabolism of heme and in the recycling of hemoglobin iron in macrophages. Homozygous heme oxygenase 1 deletion in mice leads to a paradoxical accumulation of nonheme iron in macrophages, hepatocytes, and many other cells and is associated with low plasma iron levels, anemia, endothelial cell damage, and decreased resistance to oxidative stress. A similar phenotype occurred in a child with severe heme oxygenase 1 deficiency. Recently, a mutation in the L-subunit of ferritin has been described that causes the formation of aberrant L-ferritin with an altered C-terminus. Individuals with this mutation in one allele of L-ferritin have abnormal aggregates of ferritin and iron in the brain, primarily in the globus pallidus. Patients with this dominantly inherited late-onset disease present with symptoms of extrapyramidal dysfunction. Mice with a targeted disruption of a gene for iron regulatory protein 2 (IRP2), a translational repressor of ferritin, misregulate iron metabolism in the intestinal mucosa and the central nervous system. Significant amounts of ferritin and iron accumulate in white matter tracts and nuclei, and adult IRP2-deficient mice develop a movement disorder consisting of ataxia, bradykinesia, and tremor. Mutations in the frataxin gene are responsible for Friedreich ataxia, the most common of the inherited ataxias. Frataxin appears to regulate mitochondrial iron (or iron-sulfur cluster) export and the neurologic and cardiac manifestations of Friedreich ataxia are due to iron-mediated mitochondrial toxicity. Finally, patients with Hallervorden-Spatz syndrome, an autosomal recessive, progressive neurodegenerative disorder, have mutations in a novel pantothenate kinase gene (PANK2). The cardinal feature of this extrapyramidal disease is pathologic iron accumulation in the globus pallidus. The defect in PANK2 is predicted to cause the accumulation of cysteine, which binds iron and causes oxidative stress in the iron-rich globus pallidus.
journal_name
Semin Hematoljournal_title
Seminars in hematologyauthors
Ponka Pdoi
10.1053/shem.2002.35638subject
Has Abstractpub_date
2002-10-01 00:00:00pages
249-62issue
4eissn
0037-1963issn
1532-8686pii
S0037196302500688journal_volume
39pub_type
杂志文章,评审abstract::CD59 and decay-accelerating factor (DAF) are glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins critical for regulating complement activation on the host cell surface. Defective expressions of CD59 or DAF caused by mutations in the genes coding for these proteins or genes involved in the biosyn...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2018.04.004
更新日期:2018-07-01 00:00:00
abstract::Analysis of data from 806 patients with newly diagnosed adult acute myelocytic leukemia (AML) (not including acute promyelocytic leukemia [APL] patients) treated at M.D. Anderson Cancer Center from 1995 through 1999 indicated that among patients entering a particular week of induction therapy, mortality rates were 6%,...
journal_title:Seminars in hematology
pub_type: 杂志文章
doi:10.1016/s0037-1963(01)90042-3
更新日期:2001-10-01 00:00:00
abstract::The inhibitor titer is the most important clinical measurement in inhibitor patients, and the Nijmegen method is preferable to the original and well-established Bethesda assay for this purpose; however, both methods have high inter-laboratory variability. Monitoring inhibitor patients after treatment with bypassing ag...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2008.03.002
更新日期:2008-04-01 00:00:00
abstract::Familial thrombosis has long been considered as an autosomal dominant trait, caused by a dominant gene defect with a reduced penetrance for the disease. Recently, this view has changed and today familial thrombophilia is considered as a complex genetic disorder caused by the segregation of two or more gene defects (kn...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:
更新日期:1997-07-01 00:00:00
abstract::Though peripheral T-cell lymphoma (PTCL) is an area of significant unmet therapeutic need, a number of new treatment options are available for patients, especially those with relapsed or refractory disease. A plethora of drugs are now in development for PTCL, but drugs that truly target novel disease biology are notic...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2010.01.014
更新日期:2010-04-01 00:00:00
abstract::It is now well accepted that a subgroup of patients with myelodysplastic syndromes (MDS) can recover from pancytopenia following immunosuppressive treatment (IST). For many years immunosuppression with antilymphocyte antibodies has been a standard treatment approach for patients with severe aplastic anemia (SAA). The ...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2012.07.004
更新日期:2012-10-01 00:00:00
abstract::Purine analogues have been shown to be active in a variety of B- and T-cell malignancies. Among them, pentostatin is also a tight binding inhibitor of adenosine deaminase (ADA), a key enzyme of purine metabolism. ADA is present in all human tissues, with the highest levels in the lymphoid system. Early clinical trials...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2005.12.005
更新日期:2006-04-01 00:00:00
abstract::Because optimal management of iron chelation therapy in patients with sickle cell disease and transfusional iron overload requires accurate determination of the magnitude of iron excess, a variety of techniques for evaluating iron overload are under development, including measurement of serum ferritin iron levels, x-r...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1016/s0037-1963(01)90059-9
更新日期:2001-01-01 00:00:00
abstract::Continuous daily treatment with all-trans-retinoic acid (ATRA) in patients with acute promyelocytic leukemia has been associated with a marked decline in the plasma drug concentration at the time of relapse. Recent pharmacologic studies have attempted to determine the reasons for the progressive reduction of plasma co...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:
更新日期:1994-10-01 00:00:00
abstract::Recombinant activated factor VII (rFVIIa) is being increasingly used to treat bleeding associated with a variety of non-hemophilic coagulopathic indications, and its mechanism of action in these areas is under active investigation. Numerous studies have shown that FVIIa binds with low affinity to activated platelets; ...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2008.03.013
更新日期:2008-04-01 00:00:00
abstract::During myeloid differentiation, the pluripotent hematopoietic stem cell passes through several well-defined morphologic stages within the bone marrow. These changes include progressive nuclear segmentation and the acquisition of stage-specific granules. Primary granules appear at the myeloblast stage, and are found in...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:
更新日期:1997-10-01 00:00:00
abstract::Stem cell transplantation is a recognized treatment for many hematologic malignancies. Human leukocyte antigen (HLA) testing is a key assessment in the evaluation of potential recipients and selection of the appropriate stem cell donor. Over the past several years, technological advances have moved HLA testing from a ...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1016/s0037-1963(01)90052-6
更新日期:2001-04-01 00:00:00
abstract::Imatinib (Gleevec) (formerly STI571) competitively targets the adenosine 5-triphosphate (ATP) binding site of the kinase domain of ABL and was recently approved for the treatment of chronic myeloid leukemia (CML). Point mutations occurring in the kinase domain of BCR-ABL have been identified as a cause of imatinib res...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/shem.2003.50046
更新日期:2003-04-01 00:00:00
abstract::From work particularly In the last two decades of the century, the cell populations forming blood cells can now be purified and cultured clonally so that blood cell formation can be analyzed in vitro. A large number of specific regulators of this process have been identified and mass-produced in recombinant form. Thre...
journal_title:Seminars in hematology
pub_type: 历史文章,杂志文章,评审
doi:
更新日期:1999-10-01 00:00:00
abstract::Acute myeloid leukemia (AML) is a heterogeneous disease characterized by multiple genetic and epigenetic alterations. The major causes of treatment failure remain disease relapse and treatment toxicity. However, major advances in biological determinants of disease relapse, development of targeted molecules, improvemen...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2015.03.001
更新日期:2015-07-01 00:00:00
abstract::Severe neutropenia renders patients susceptible to life-threatening bacterial and fungal infections. Despite improvements in supportive care and antimicrobial therapy, morbidity and mortality remains significant. Since the 1960s, granulocyte transfusions have been used to either treat or prevent serious infections in ...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2019.11.002
更新日期:2019-10-01 00:00:00
abstract::In previous studies, treatment with epoetin alfa facilitated preoperative donation of autologous blood (AB). However, some patients may not be able to donate sufficient AB to meet their surgical blood requirements when the time to surgery is short. In this multicenter, double-blind, placebo-controlled study, the abili...
journal_title:Seminars in hematology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:
更新日期:1996-04-01 00:00:00
abstract::The farnesyltransferase inhibitors (FTIs) have been shown in early clinical trials to elicit antitumor actions in a broad range of solid and hematologic malignancies. The mechanism of FTI action involves blockade of farnesyltransferase, an enzyme implicated in multiple cell-signaling pathways involved in proliferation...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/shem.2002.35984
更新日期:2002-07-01 00:00:00
abstract::Seventy-six patients with previously untreated advanced Hodgkin's disease have been treated with the MOPP/ABV (mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vincristine) hybrid program. Ten patients also received involved field radiation to the mediastinum for residual nodal disease af...
journal_title:Seminars in hematology
pub_type: 杂志文章
doi:
更新日期:1987-04-01 00:00:00
abstract::A new high-purity recombinant factor VIII preparation has been developed for the treatment of hemophilia A. Structurally, this factor VIII preparation, B-domain deleted recombinant factor VIII (BDDrFVIII), differs from other recombinant and plasma-derived factor VIII preparations in that most of the B-domain has been ...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1016/s0037-1963(01)90103-9
更新日期:2001-04-01 00:00:00
abstract::The central hypothesis of our laboratory research program in large granular lymphocyte (LGL) leukemia is that leukemic LGL represent antigen-driven cytotoxic T lymphocytes (CTL) with characteristics of dysregulated apoptosis. The clinical features of LGL leukemia highlight the association of autoimmune diseases such a...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1016/s0037-1963(03)00135-5
更新日期:2003-07-01 00:00:00
abstract::Trauma is rapidly replacing stroke and cardiovascular disease as a leading cause of death in Western countries such as the United States, and almost a third (30%) of trauma deaths are due to blood loss. Although the new intervention strategies that have been developed and adopted by emergency care staff have reduced t...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2003.11.009
更新日期:2004-01-01 00:00:00
abstract::Thrombocytopenia is common among sick neonates, affecting 20% to 35% of all patients admitted to the neonatal intensive care unit (NICU). While most cases of neonatal thrombocytopenia are mild or moderate and resolve within 7 to 14 days with appropriate therapy, 2.5% to 5% of NICU patients develop severe thrombocytope...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2010.04.002
更新日期:2010-07-01 00:00:00
abstract::By definition, myeloproliferative disorders (MPDs) are caused by an acquired somatic mutation of a hematopoietic progenitor/stem cell and have sporadic occurrence. However, well-documented families exist with first-degree relatives acquiring one or several MPDs. It is reasonable to assume that the germ-line mutation(s...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2005.08.002
更新日期:2005-10-01 00:00:00
abstract::Imatinib (Gleevec) (formerly STI571) is an orally bioavailable rationally developed inhibitor of the tyrosine kinases Bcr-Abl, Kit, and platelet-derived growth factor receptor (PDGFR). In 4 years of clinical development, more than 12,000 patients have been treated in the clinical development program. Imatinib was firs...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/shem.2003.50037
更新日期:2003-04-01 00:00:00
abstract::This phase I trial of idarubicin (IDA) was conducted in 32 patients with acute leukemia and chronic myelogenous leukemia (CML) in blastic crisis (CML/BC) who either had failed to achieve a complete remission (CR) after initial induction therapy or had relapsed after CR. IDA was administered at dosages ranging from an ...
journal_title:Seminars in hematology
pub_type: 临床试验,杂志文章,评审
doi:
更新日期:1996-10-01 00:00:00
abstract::There are now more than 25 million volunteer donors registered worldwide for patients in need of a life-saving hematopoietic cell transplant to cure blood disorders. Although a human leukocyte antigen (HLA)-matched donor remains the preferred stem cell source for transplantation, the use of a donor with limited HLA mi...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2016.07.003
更新日期:2016-10-01 00:00:00
abstract::Acute promyelocytic leukemia (APL) is characterized by reciprocal chromosomal translocations that always Involve the retinoic acid receptor-alpha (RARalpha) gene on chromosome 17. RARalpha variably fuses to the PML, PLZF, NPM, NuMA, and STAT 5b genes (X genes), leading to the generation of X-RARalpha and RARalpha-X fu...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1016/s0037-1963(01)90006-x
更新日期:2001-01-01 00:00:00
abstract::For the majority of hematologic malignancies allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment option. Sibling donors have been the standard for adult patients. Since there is not a suitable family donor for all patients, the need for alternative donors for HCT is great. Fortunately, t...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2016.01.009
更新日期:2016-04-01 00:00:00
abstract::The molecular causes of hereditary spherocytosis (HS) have been unraveled in the past decade. No frequent defect is found, and nearly every family has a unique mutation. In dominant HS, nonsense and frameshift mutations of ankyrin, band 3, and beta-spectrin predominate. Recessive HS is most often due to compound heter...
journal_title:Seminars in hematology
pub_type: 杂志文章,评审
doi:10.1053/j.seminhematol.2004.01.002
更新日期:2004-04-01 00:00:00