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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe congenital neutropenia (CN) is characterized by a maturation arrest of myelopoiesis at the promyelocyte stage. Treatment with pharmacological doses of recombinant human granulocyte colony-stimulating factor (rh-G-CSF) stimulates neutrophil production and decreases the risk of major infectious complications. However, approximately 15% of CN patients develop myeloid malignancies that have been associated with somatic mutations in the G-CSF receptor (G-CSFR) and RAS genes as well as with acquired monosomy 7. We report a CN patient with chronic myelomonocytic leukemia (CMML) who never received rh-G-CSF. Molecular analysis demonstrated a somatic G-CSFR mutation (C2390T), which led to expression of a truncated G-CSFR protein in the CMML. Normal G-CSFR expression was unexpectedly absent in primary and cultured CMML. In addition, CMML cells showed monosomy 7 and an oncogenic NRAS mutation. In vitro culture revealed a G-CSF-dependent proliferation of CMML cells, which subsequently differentiated along the monocytic/macrophage lineage. Our results provide direct evidence for the in vivo expression of a truncated G-CSFR in leukemic cells, which emerged in the absence of rh-G-CSF treatment and transduces proliferative signals.
Leukemia 2005 Apr
PMID:An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia. 1572 85

We analyzed the structure of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a 6-year-old female patient with severe congenital neutropenia (SCN) who experienced severe recurrent infections since 1 month of age. There is no family history of any similar disease. When the patient was 4 months old, she began receiving treatment with recombinant human G-CSF that resulted in a small increase in the neutrophil count sufficient for the prevention and treatment of bacterial infection. An analysis of complementary DNA for the patient's G-CSF receptor revealed a 3-base pair deletion in the juxtamembrane intracellular sequence. This deletion at the beginning of exon 16 was thought to be caused by alternative splicing; analysis of the DNA revealed a G-to-A point mutation of the final nucleotide of intron 15. To evaluate the functional activity of the G-CSF receptor with this 3-base pair deletion of the juxtamembrane region, we transfected this G-CSF receptor mutant into an interleukin 3-dependent cell line, BAF/3. BAF/3 cells expressing the mutant G-CSF receptor showed augmented proliferation activity in response to G-CSF compared with cells having the wild-type G-CSF receptor. Although the proliferation signal of G-CSF in normal hematopoiesis is transduced through the activation of MAP kinases, this G-CSF receptor mutant showed decreased activation of ERKI/2 in response to G-CSF compared with the wild type, but the transduced sig-nal for Stat3 activation by G-CSF was of the same magnitude as that of the wild-type G-CSF receptor. This result means that the augmented proliferation activity in response to G-CSF that we observed in cells having the G-CSF receptor gene with the 3-base pair deletion is transduced through an intracellular signaling pathway other than MAP kinase. Because SCN patients with a mutation in the G-CSF receptor frequently develop leukemia, this 3-base pair deletion in the juxtamembrane sequence of the G-CSF receptor gene in this patient may be one step in the course of leukemic transformation.
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PMID:A novel mutation in the juxtamembrane intracellular sequence of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a patient with severe congenital neutropenia augments GCSF proliferation activity but not through the MAP kinase cascade. 1622 88

The growth factor independence-1 (Gfi1) transcription factor is required for proper development of neuroendocrine cells, sensory neurons, and blood. Patients with mutations in Gfi1 exhibit severe congenital neutropenia (SCN) or non-immune chronic idiopathic neutropenia of adults. Gfi1 was initially described as an oncoprotein that mediates tumor progression in a mouse model of leukemia; however, recent data suggest that Gfi1 may act as either an oncogene or an anti-proliferative tumor suppressor gene depending on the cell type. Here we review the latest literature on Gfi1, and emphasize its role in the hematopoietic, sensory and neuroendocrine systems.
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PMID:The growth factor independence-1 transcription factor: new functions and new insights. 1671 99

Severe congenital neutropenia (CN) includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. CN with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of CN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60% to 80% of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, granulocyte colony-stimulating factor (G-CSF) receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrate that, regardless of the particular CN subtype, more than 95% of these patients respond to recombinant human (rHu)G-CSF with ANCs that can be maintained above 1.0 x 10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into myelodysplasia (MDS)/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC >1,000/microL) in the risk of developing acute myeloid leukemia (AML) has been reported. Hematopoietic stem cell transplantation (HSCT) is still the only treatment available for patients who are refractory to G-CSF treatment.
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PMID:Severe congenital neutropenia. 1682 61

We report a case of a child with severe congenital neutropenia (Kostmann's syndrome) who was treated with daily prophylactic subcutaneous granulocyte colony-stimulating factor (G-CSF) from the age of eight to sixteen years before being discontinued for poor haematological and clinical response. She did not have a HLA-matched sibling to enable bone marrow transplantation. She subsequently developed acute megakaryoblastic leukemia at the age of 17 years and succumbed during induction chemotherapy. The role of G-CSF in the pathogenesis of her malignant transformation to AML is complicated as this disorder has a propensity for myelodysplasia or AML as part of its natural history.
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PMID:Malignant myeloid transformation in a child with severe congenital neutropenia (Kostmann's syndrome). 1689 20

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

Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
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PMID:Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. 1749 58

The inherited bone marrow failure syndromes are traditionally considered to be pediatric disorders, but in fact, many of the patients now are diagnosed as adults, and many diagnosed as children now live to reach adulthood. The most common of these rare disorders include Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome and amegakaryocytic thrombocytopenia, which often develop aplastic anemia and may evolve into myelodysplastic syndrome and acute myeloid leukemia; and Diamond-Blackfan anemia, severe congenital neutropenia, and thrombocytopenia absent radii, single cytopenias that rarely if ever become aplastic but have increased risks of leukemia. In addition, the first three syndromes have high risks of solid tumors: head and neck and anogenital squamous cell carcinoma in Fanconi anemia and dyskeratosis congenita, and osteogenic sarcoma in Diamond-Blackfan anemia. Diagnosis of a marrow failure syndrome requires recognition of characteristic physical abnormalities when present, and consideration of these disorders in the differential diagnosis of patients who present with "acquired" aplastic anemia, myelodysplastic syndrome, acute myeloid leukemia, or atypically early cancers of the types seen in the syndromes. Ultimate proof will come from identification of pathogenic mutations in genes associated with each syndrome.
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PMID:Diagnosis, genetics, and management of inherited bone marrow failure syndromes. 1802 6

Congenital neutropenia are extremely rare diseases, defined by a permanent or cyclic decrease of blood neutrophils. Molecular basis of several congenital neutropenia has been recently determined, involving gene coding for the neutrophil elastase gene (ELA2), GFI1, WAS protein and mitochondrial HAX1 protein. These mutations, dominant (ELA2, GFI1), X-linked (WAS) and autosomal recessive (HAX1), result in instability of the contents of the granules- particularly the neutrophil elastase- or in abnormalities of the cytoskeleton, and possibly, in an increased apoptosis. ELA2 mutations resulting both in profound and permanent neutropenia, and in cyclic--pseudo sinusoidal--neutropenia lead to consider that time pattern is very close in the two apparently distinct phenotypes. This observation suggests that temporal variations of neutrophils could be represented by non linear functions. Congenital neutropenia, specifically ELA2 mutated, are also characterized by a high rate of leukemia (about 15% at 20 years of age). Leukemia risk does not appear to be related to an oncogenic effect of ELA2 mutations, but much likely to the deepness of the neutropenia, and the intensity of G-CSF therapy.
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PMID:[Granulopoeisis and leukemogenesis: lessons from congenital neutropenia]. 1833 77

Congenital neutropenia syndromes comprise a heterogeneous group of inherited disorders. Hereditary conditions associated with low neutrophil counts are persistent and need to be differentiated from neutropenia secondary to autoimmune processes or other pathologic conditions, such as myelodysplasia or leukemia. Clinically, congenital neutropenia is characterized by recurrent bacterial infections. Recently, several novel genetic defects were described in patients with congenital neutropenia, shedding light on the pathophysiology of these rare diseases.
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PMID:Congenital neutropenia syndromes. 1842 32


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