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)

Severe congenital neutropenia (SCN) is a syndrome characterized by an isolated block in granulocytic differentiation and an increased risk of developing acute myeloid leukemia (AML). Recent studies have demonstrated that the majority of patients with SCN and cyclic neutropenia, a related disorder characterized by periodic oscillations in the number of circulating neutrophils, have heterozygous germline mutations in the ELA2 gene encoding neutrophil elastase (NE). To test the hypothesis that these mutations are causative for SCN, we generated transgenic mice carrying a targeted mutation of their Ela2 gene ("V72M") reproducing a mutation found in 2 unrelated patients with SCN, one of whom developed AML. Expression of mutant NE mRNA and enzymatically active protein was confirmed. Mice heterozygous and homozygous for the V72M allele have normal numbers of circulating neutrophils, and no accumulation of myeloid precursors in the bone marrow was observed. Serial blood analysis found no evidence of cycling in any of the major hematopoietic lineages. Rates of apoptosis following cytokine deprivation were similar in wild-type and mutant neutrophils, as were the frequency and cytokine responsiveness of myeloid progenitors. The stress granulopoiesis response, as measured by neutrophil recovery after cyclophosphamide-induced myelosuppression, was normal. To define the leukemogenic potential of V72M NE, a tumor watch was established. To date, no cases of leukemia have been detected. Collectively, these data suggest that expression of V72M NE is not sufficient to induce an SCN phenotype or leukemia in mice.
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PMID:Mice expressing a neutrophil elastase mutation derived from patients with severe congenital neutropenia have normal granulopoiesis. 1238 20

Kostmann syndrome (KS) is an inherited hematological disorder characterized by an absolute neutrophil count (ANC) <0.2 x 109/L and life-threatening bacterial infections. Granulocyte-colony stimulating factor (G-CSF) makes it possible to reach an ANC of 1.0 x 109/L and consequently to reduce significantly the occurrence of severe infections. Absence of response to G-CSF, G-CSF receptor mutation, and leukemic transformation are absolute indications to perform hematopoietic stem cell transplantation (HSCT). Pulmonary mycosis does not represent an absolute contraindication to bone marrow transplantation (BMT), although a relapse rate of 30-50% has been reported, despite adequate medical and surgical treatment. Mycotic pneumonia recurrence shows a mortality rate above 80%, especially in the presence of persisting immunosuppression. We report on a KS patient with long-lasting fungal pneumonia who developed myelodysplasia and subsequent acute myeliod leukemia (AML) conversion resistant to antiblastic therapy. Despite surgical excision and secondary prophylaxis, recurrence of the pulmonary lesion occurred prior to the unrelated HSCT. In spite of these poor prognostic characteristics, outcome was uneventful and the patient is alive and well in continuous complete remission with no signs of fungal infection.
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PMID:Uneventful outcome of unrelated hematopoietic stem cell transplantation in a patient with leukemic transformation of Kostmann syndrome and long-lasting invasive pulmonary mycosis. 1269 70

Severe congenital neutropenia (SCN), a heterogeneous disorder that includes Kostmann syndrome, predisposes to myelodysplasia and acute myelogenous leukemia. Recently identified heterozygous mutations in the gene ELA2, encoding neutrophil elastase on human chromosome 19pter, account for the majority of autosomal dominant cases of SCN, including those demonstrating neoplastic progression. The involvement of the serine protease neutrophil elastase, localized to the granules of neutrophils and monocytes, implies an unexpected role for proteolytic regulation of hematopoiesis. Continued elucidation of the clinical features, molecular genetics, and biochemistry is likely to provide insight into novel pathways of leukemia induction with attendant prospects for new avenues of therapy.
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PMID:Leukemia in severe congenital neutropenia: defective proteolysis suggests new pathways to malignancy and opportunities for therapy. 1453 48

Congenital neutropenia is strictly defined as neutropenia present at birth. However, it is more generally used to describe neutropenia secondary to inherited genetic mutations. This review will discuss the presentation of such children and the various causes of congenital neutropenia. In particular, it will focus on severe congenital neutropenia (SCN) and the recent discovery of mutations in the gene encoding neutrophil elastase in the majority of cases of SCN. The potential mechanisms of pathogenesis and of transformation to leukaemia will be discussed. Shwachman-Diamond Syndrome and other less common causes of congenital neutropenia will also be reviewed. Finally, an approach to the child with potential congenital neutropenia will be presented.
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PMID:Congenital neutropenia. 1455 75

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor alpha (CBFalpha). In mice, CBFalpha regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFalpha regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/beta-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFalpha binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFalpha co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFalpha activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFalpha to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.
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PMID:Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. 1459 2

The term congenital neutropenia (CN) has been used for a group of hematologic disorders characterized by severe neutropenia with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L associated with increased susceptibility to bacterial infections. This group of diseases includes primary bone marrow failure syndromes with isolated neutropenias and neutropenias associated with metabolic or immunologic disorders or with a complex syndrome. To avoid confusion, we prefer using the term CN only for the most severe disorder among this group: severe neutropenia characterized by an early stage maturation arrest of myelopoiesis leading to bacterial infections from early infancy. This disease has originally been described as Kostmann syndrome with an autosomal recessive inheritance. Recent pathogenetic investigations have demonstrated that this clinical phenotype includes also autosomal dominant and sporadic cases with different point mutations in the neutrophil elastase gene in a subgroup of patients. Data on over 400 patients with CN collected by the Severe Chronic Neutropenia International Registry demonstrate that independent from the CN-subtype more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (rHuG-CSF filgrastim, lenograstim) with ANC that can be maintained around 1.0 x 10(9)/L. Adverse events include mild splenomegaly, moderate thrombocytopenia, osteoporosis and malignant transformation into myelodysplastic syndrome/leukemia. Development of additional genetic aberrations, e.g., G-CSF-receptor gene mutations, monosomy 7 or ras mutations during the course of the disease indicate an underlying genetic instability leading to an increased risk of malignant transformation. If and how G-CSF treatment impacts on these adverse events remains unclear since there are no historical controls for comparison. Hematopoietic stem cell transplantation is still the only available treatment for patients refractory to G-CSF treatment.
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PMID:Congenital neutropenias. 1469 35

The granulocyte colony-stimulating factor (G-CSF) plays an important role in normal granulopoiesis. Its functions are mediated by specific receptors on the surface of responsive cells and, upon ligand binding, several cytoplasmic tyrosine kinases are activated. The cytoplasmic region proximal to the membrane of the G-CSF receptor (G-CSF-R) transduces proliferative and survival signals, whereas the distal carboxy-terminal region transduces maturation signals and suppresses the receptor's proliferative signals. Mutations in the G-CSF-R gene resulting in truncation of the carboxy-terminal region have been detected in a subset of patients with severe congenital neutropenia who developed acute myelogenous leukemia (AML). In addition, the AML1-ETO fusion protein, expressed in leukemic cells harboring the t(8;21), disrupt the physiological function of transcription factors such as C/EBPalpha and C/EBPepsilon, which in turn deregulate G-CSF-R expression. The resulting high levels of G-CSF-R and G-CSF-dependent cell proliferation may be associated with pathogenesis of AML with t(8;21). Moreover, in vitro and in vivo studies demonstrated that G-CSF may act as a co-stimulus augmenting the response of PML-RARalpha acute promyelocytic leukemia cells to all-trans-retinoic acid treatment. Finally, in the PLZF-RARalpha acute promyelocytic leukemia transgenic model, G-CSF deficiency suppressed leukemia development. Altogether, these data suggest that the G-CSF signaling pathway may play a role in leukemogenesis.
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PMID:Granulocyte colony-stimulating factor and leukemogenesis. 1522 4

Congenital neutropenia predisposes to the development of haematopoetic malignancies. We present a 3,5-year child, diagnosed with congenital neutropenia at the age of I month. The diagnosis was based on peripheral blood and bone marrow aspirate analyses, performed after the treatment of multiple axillar abscesses. Recurrent infections were treated with broad-spectrum antibiotics and leukocyte colony stimulating factors. At the age of 19 months during routine check-up the child presented with gingival hypertrophy, fragility and bleeding. The histopathological analysis of gingival biopsy was consisted with the diagnosis of Langerhans cell histiocytosis. The child was treated according to LCH protocol for therapeutic group C. After 12 months of such chemotherapy, the follow-up histopathological analysis of gingival biopsy revealed the presence of Langerhans cells, which was the indication for chemotherapy prolongation (6 additional VP courses). Chemotherapy was completed after 6 additional courses and the disease remission was confirmed by histopathological analysis of gingival biopsy. Congenital neutropenia predisposes to myeloproliferative disorders, particularly to childhood myeloblastic leukemia. Based on the presented case report we would like to emphasize the possibility of other hematological syndromes development.
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PMID:[Langerhans cell histiocytosis in a child with congenital neutropenia]. 1530 29

Our objective was to study the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with severe congenital neutropenia (SCN). Among 101 cases of SCN included in the French Severe Chronic Neutropenia Registry, nine patients received HSCT between 1993 and 2003, in seven institutions. The indications were nonresponse to G-CSF therapy in four cases, bone marrow failure in one case, and myelodysplastic syndrome or leukemia in four cases. The conditioning regimen consisted of total body irradiation in two cases and chemotherapy alone in the other seven cases. Seven patients received stem cells from unrelated donors and two from identical siblings. Engraftment occurred in all but one of the patients. Three patients died. The respective causes of death were graft-versus-host disease, infection, and EBV post-transplant lymphoproliferative disease. Six patients are alive and in complete remission, with a median follow-up of 3.1 years. These results indicate that HSCT is feasible for patients with SCN who do not respond to G-CSF, who have malignant transformation, or who are at a high risk of malignant transformation, even if an HLA-identical sibling donor is not available.
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PMID:Hematopoietic stem cell transplantation in severe congenital neutropenia: experience of the French SCN register. 1548 67

Many leukemia and cancer cells exhibit constitutive activation of STAT5, which was suggested to provide an anti-apoptotic advantage. Transformation of cytokine-dependent hematopoietic cells, such as Ba/F3 cells to autonomous growth and tumorigenicity equally results in selection for constitutive activation of STAT5. We compared STAT5 signaling between erythropoietin(Epo)-dependent cells and cells that were transformed by oncogenic activation of the erythropoietin receptor (EpoR) by coexpression of the gp55-P envelope protein of the spleen focus forming virus or by expression of the R129C constitutively active EpoR mutant. In transformed cells it was mainly STAT5B that was constitutively activated. In contrast, Epo stimulation activated both STAT5A and STAT5B. In transformed cells, chromatin immunoprecipitation (ChIP) showed STAT5 to be physically bound to promoters of STAT5 target genes, such as Bcl(XL), and to be able to promote transactivation of the Bcl(XL) promoter in a constitutive fashion. Sequencing of native sequences after ChIP with anti-STAT5 antibodies in Epo-dependent and -transformed cells indicated that in gp55-transformed cells, STAT5B bound in the chromatin not only to N3 high affinity, but also to low affinity N4 GAS sites. Transactivation for N3 GAS sites in luciferase reporters was specific to gp55 transformation. Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.
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PMID:Differential STAT5 signaling by ligand-dependent and constitutively active cytokine receptors. 1567 77


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