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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.
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PMID:Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia. 854 48

The use of colony-stimulating factors (CSFs) in acute myeloid leukemia (AML) remains controversial. Potential uses include shortening the period of neutropenia, inducing leukemic cells into the S-phase of the cell cycle, stem cell protection, inducing differentiation of leukemic cells, interrupting autocrine/paracrine loops, direct inhibition of leukemogenesis, and enhancing antimicrobial function. Data from the nine controlled studies of CSFs that have been reported between 1990 and 1995, with varying patient characteristics and other factors, indicate that growth factors have several uses in AML therapy. The published literature now suggests that the safety of CSFs is no longer a major clinical concern, and significant experience has been gained in reducing the period of neutropenia following induction therapy. Yeast-derived granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor appear to be effective and probably have an important role in the management of older adult patients with AML and for those patients with a significant risk for therapy-related morbidity and mortality. The use of CSFs as priming agents remains experimental; results of further prospective placebo-controlled studies, with laboratory correlates, are awaited.
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PMID:Use of growth factors during induction therapy for acute myeloid leukemia. 861 71

Severe congenital neutropenia (SCN) is a heterogeneous disease condition with a variable family history and a propensity to progress towards myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). In a subgroup of patients, point mutations in the G-CSF-R gene have been found. These nonsense mutations result in the truncation of the C-terminal cytoplasmic region, a subdomain that is crucial for G-CSF induced maturation. SCN patients with mutations in the G-CSF-R gene appear to be predisposed to develop AML. Here, we recapitulate our view of how defective G-CSF-R may contribute to neutropenia and leukemogenesis.
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PMID:Severe congenital neutropenia terminating in acute myeloid leukemia: disease progression associated with mutations in the granulocyte-colony stimulating factor receptor gene. 891 14

In the early stages of the development of granulocytic colony-stimulating factors (G-CSF and GM-CSF) in oncology and hematology, myeloid malignancies were considered to be a contraindication to their use. In fact, myeloid leukemic cells bear specific receptors for G-CSF and GM-CSF and these CSFs induce an in vitro proliferation in primary blast cells of most patients with acute myeloid leukemia (AML). In addition, autocrine or paracrine loops of stimulation have been demonstrated in some cases. Despite these theoretical risks of blast proliferation, G-CSF and GM-CSF have been extensively tested in patients with AML or myelodysplastic syndromes. Major objectives were the correction of acquired or chemotherapy-induced neutropenia, but also the reinforcement of the antileukemic efficacy of cytotoxic agents. Recently, G-CSF has also been used to mobilize hematopoietic progenitors in the peripheral blood. Major results of several double-blind clinical trials are the demonstration of the safety of CSF administration in these patients, since no risk of in vivo blast cell regrowth has been observed, and their efficacy to shorten the duration of chemotherapy-induced neutropenia. However, no significant reduction in the treatment-related mortality and no survival improvement were afforded by the use of these CSFs. From another point of view, the search for AML-specific CSF-receptor or CSF-receptor associated molecule abnormalities represents a new promising area to try to understand the mechanisms of leukemogenesis.
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PMID:Granulocytic colony-stimulating factors in the management of patients with acute myeloid leukemia. 897 86

Kostmann Syndrome is defined as a chronic neutropenia, dating from early childhood, characterized typically by a granulopoeisis impairment at the promyelocyte stage. The origin is not yet understood. G-CSF receptor anomaly -the intra-cellular carboxy terminal region- was noted in a few patients (6 out of 54), initially in two patients who later developed secondary leukemia. More follow-up, with other patients, led us to consider the mutation of the G-CSF receptor sometimes as a transient event, not systematically resulting in malignancy. This finding directs research toward intra-cellular signaling pathway in a pathology that raises questions both of granulopoeisis and leukemogenesis.
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PMID:Pathophysiology of Kostmann syndrome: the G-CSF receptor issue. 916 8

Granulocyte colony-stimulating factor (G-CSF) exerts its biologic effects through binding to its receptor expressed on myeloid cells. Like other cytokines, G-CSF induces intracellular protein tyrosine phosphorylation and activates various signaling cascades. Activation of JAK tyrosine kinases and signal transducers and activators of transcription (STAT) proteins as well as activation of the ras-MAP kinase route results in induction of gene transcription. Distinct regions or defined tyrosine residues of the G-CSF receptor cytoplasmic domain are required for complex formation with specific signaling molecules and ultimately regulate proliferation and maturation of myeloid cells. In vivo, administration of G-CSF results in increased numbers of neutrophils in normal individuals, in patients with chemotherapy-induced neutropenia, and in patients with chronic neutropenia. A subgroup of patients with severe congenital neutropenia displayed point mutations in the cytoplasmic region of the G-CSF receptor: These G-CSF receptor mutations might be involved in leukemogenesis in congenital neutropenia.
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PMID:Advances in understanding postreceptor signaling in response to granulocyte colony-stimulating factor. 920 32

The granulocyte colony-stimulating factor receptor (G-CSFR) critically regulates granulopoiesis. Defects in G-CSFR expression due to targeted disruption of the G-CSFR gene or the genes for the transcription factors C/EBPalpha and PU.1 result in decreases in hematopoietic progenitor cell numbers and neutropenia. Mutations in the G-CSFR gene disrupt its normal signaling functions and appear to contribute to leukemogenesis. Acquired mutations in the G-CSFR resulting in truncation of the distal cytoplasmic region that mediates maturation and growth arrest signaling have been reported in patients with severe congenital neutropenia (SCN) and acute myelogenous leukemia (AML). A role for G-CSFR mutations in the pathogenesis of other disorders is speculated. This review will summarize the current state of knowledge of the G-CSFR and its role in disorders of granulopoiesis.
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PMID:The granulocyte colony-stimulating factor receptor and its role in disorders of granulopoiesis. 951 98

Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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PMID:Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias. 1145 19

The spectrum of large granular lymphocyte (LGL) proliferations consists of four distinct entities: reactive/transient LGL expansion, chronic LGL lymphocytosis, classical indolent LGL leukemia, and aggressive LGL leukemia. LGL leukemias are classified as lymphoid malignancies. They are divided into CD3(+)/T-cell LGL (85% of cases) and CD3(-)/natural killer (NK) cell LGL leukemia (15% of cases). Recent progress in the comprehension of the leukemogenesis has shown a dysregulation of survival signals in leukemic cells. Identification of LGL expansion has been improved using T-cell receptor (TCR)beta/gamma polymerase chain reaction (PCR) analysis and a combination of Vbeta and killer cell immunoglobulin-like receptor (KIR)-specific monoclonal antibodies. LGL leukemias are characterized by a clonal LGL infiltration of the bone marrow, spleen, and liver. Monoclonality is recognized by phenotypic, molecular, and karyotypic analysis. T-LGL leukemias affect the elderly and display a relatively indolent behavior. Approximately 60% to 70% of patients are symptomatic: recurrent infections secondary to chronic neutropenia, anemia, and autoimmune disease such as rheumatoid arthritis are the main clinical manifestations. Long-lasting remission can be obtained with low-dose methotrexate, cyclosporine A, or cyclophosphamide. Conversely, NK LGL leukemias behave aggressively, and most patients do not respond to chemotherapy.
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PMID:Clinical features of large granular lymphocyte leukemia. 1287 67

Point mutations in the gene for the granulocyte colony-stimulating factor (G-CSF) receptor CSF3R have been implicated in the progression of severe congenital neutropenia (CN) to leukemia. In this study we present data on a total of 218 patients with chronic neutropenia, including 148 patients with CN (23/148 with secondary malignancies). We detected CSF3R nonsense mutations at 17 different nucleotide positions (thereof 10 new mutations) which lead to a loss of 1 to all 4 tyrosine residues in the intracellular domain of the receptor. Of 23 patients with CN with signs of malignant transformation, 18 (78%) were shown to harbor a CSF3R mutation, indicating that these mutations, although not a necessary condition, are highly predictive for malignant transformation even if detected in a low percentage of transcripts. In serial analyses of 50 patients with CSF3R mutations we were able to follow the clonal dynamics of mutated cells. We could demonstrate that even a highly clonal hematopoiesis did not inevitably show a rapid progression to leukemia. Our results strongly suggest that acquisition of a CSF3R mutation is an early event in leukemogenesis that has to be accompanied by cooperating molecular events, which remain to be defined.
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PMID:Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. 1698 78


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