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Biomedical subjects

Rosemary E Gale

Publications and source records attributed to Rosemary E Gale.

10 recordsLinked to original sources
PubMed2003

Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy.

Severe congenital neutropenia (SCN) is characterized by profound neutropenia, recurrent severe bacterial infections and maturation arrest in the myeloid lineage. Granulocyte colony-stimulating factor (G-CSF) treatment results in clinical improvement in over 90% of cases. Point mutations of the G-CSF receptor (G-CSFR) have been implicated in the progression of SCN to acute myeloid leukaemia (AML). Data are presented here on the 9-year follow-up of seven patients and the further screening of 18 other cases. One of the two original cases with a G-CSFR mutation has improved clinically; nevertheless, mutant DNA could still be detected at a very low level > 8 years after identification. The second child with a mutation progressed to myelodysplasia/AML 5 years after her mutation was detected. No mutations were found in the 18 new cases. One of three transformed cases had a G-CSFR mutation. This work is in agreement with the suggestion that G-CSFR mutations may provide a survival advantage to haemopoietic stem cells, but argues against the inevitability of leukaemic progression in their presence. Furthermore, the low frequency of G-CSFR mutations in SCN and the importance of regular screening and close clinical and laboratory follow-up if a mutation is found were demonstrated.

Acute Disease↗
PubMed2003

Neutrophil elastase mutations in congenital neutropenia.

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Autosomal dominant and sporadic forms of the disease have subsequently been recognized. All forms of the disease are manifest by persistent severe neutropenia and recurrent bacterial infection. Cyclical neutropenia (CyN) is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, heterozygous mutations in the ELA2 gene encoding neutrophil elastase (NE) have been described in the majority of cases of CyN and sporadic and autosomal dominant SCN. A case of paternal mosaicism has provided genetic "proof" of the pathogenicity of such mutations, but the exact pathogenic mechanism remains elusive. This review will focus on the mosaic proof and examine possible pathogenic mechanisms. The lack of obvious associations and indeed overlap between the mutations that cause the two diseases will also be discussed. Clinically to date, the discovery of an elastase mutation has been of limited value to individual patients. However, it is hoped that further genotype/phenotype studies may improve assessment of patient prognosis.

Amino Acid Substitution↗
PubMed2003

Prognostic implications of the presence of FLT3 mutations in patients with acute myeloid leukemia.

Several studies have shown that mutations in the FLT3 gene are common events in AML, with approximately one third of adult patients harbouring either an internal tandem duplication in the juxtramembrane domain or a D835 mutation in the kinase domain. The majority of studies in pediatric and adult AML have shown that FLT3 mutations are powerful prognostic factors predicting for increased relapse risk and adverse overall survival. Some reports have suggested that loss of the wild type allele might be associated with an even worse prognosis. Changes in the pattern of FLT3 mutations between disease presentation and relapse restrict their value as a marker of minimal residual disease, and have significant implications for therapy. The optimum treatment for patients with FLT3 mutations remains unknown and large prospective studies are warranted to evaluate the efficacy of various treatment modalities such as bone marrow transplantation and targeted therapy with tyrosine kinase inhibitors.

Adult↗
PubMed2003

Pathogenic markers in essential thrombocythemia.

Although long recognized as a clinical entity, the diagnosis of essential thrombocythemia (ET) still relies on the exclusion of reactive conditions and other myeloproliferative disorders. Recent studies have attempted to identify new markers for this disorder and suggest that part of the problem may relate to its heterogeneity. Cytogenetic abnormalities are rare, but analysis using X-chromosome inactivation patterns indicates that nearly 50% of evaluable patients have polyclonal myelopoiesis and this is associated with a lower risk of thrombosis. Reduced and heterogeneous staining of c-Mpl in bone marrow biopsies may help to distinguish ET and a reactive thrombocytosis. Increased expression of PRV-1 (polycythemia ruba vera) in granulocytes may assist in discriminating between polycythemia vera and at least some cases of ET. The contribution of these markers to disease pathogenesis is unknown and prospective studies are needed to evaluate their usefulness for predicting clinical outcome and directing patient therapy.

Biomarkers↗
PubMed2002

Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors.

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835(+), 2 ITD(+)), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD(+), 2 D835(+)), 5 who were all originally ITD(+) had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease.

Base Sequence↗
PubMed2002

An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia.

To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3. We describe here a Thr617Asn mutation in the transmembrane domain of the non-tyrosine kinase receptor for granulocyte colony-stimulating factor (G-CSF) in the blast cells of two out of 555 AML patients examined. The mutant receptor conferred growth factor independence on factor-dependent Ba/F3 cells. In the absence of ligand, immunoblotting showed weak phosphorylation of JAK2, STAT3, ERKs 1 and 2 and the receptor itself, and there was approximately 70% of maximal growth in a proliferation assay. All signals were significantly enhanced in the presence of G-CSF. Retroviral transduction of mutant receptor into primary hematopoietic CD34+ cells induced G-CSF independent myeloid differentiation as assessed by the development of neutrophils and surface expression of CD11b and CD14. These results confirm the importance of the transmembrane domain for receptor function and suggest that introduction of an asparagine residue can cause sufficient stabilization of helix-helix interactions in the absence of ligand to activate downstream signaling pathways involved in directing proliferation and differentiation.

Acute Disease↗
PubMed2002

Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.

Heterozygous mutations in neutrophil elastase have been detected in many sporadic cases of congenital neutropenia. However, a convincing pathogenetic mechanism has not been established, and it is unclear whether the effects of the mutant enzyme occur within the cell of production or are paracrine in nature. The healthy father of a patient was demonstrated to be mosaic for his daughter's Cys42Arg elastase mutation. Using semiquantitative polymerase chain reaction, approximately half of his T cells were shown to carry the mutation in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wild type. These results demonstrate that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. This is the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggests that the mutant elastase does not have paracrine effects.

Adult↗
PubMed2002

Mutations of the AML1 gene in acute myeloid leukemia of FAB types M0 and M7.

The AML1 gene encodes a transcription factor that, together with its heterodimeric partner CBFB, regulates a number of target genes that are essential for normal hemopoiesis. In acute myeloid leukemia (AML), AML1 is disrupted not only by chromosomal translocations but also by mutations in the runt domain, which binds both DNA and CBFB. Acquired mutations have been described predominantly in the AML FAB type M0. To date, most patients appear to have biallelic disease, suggesting a complete lack of normal AML1 function. Inherited loss of function mutations thought to lead to haploinsufficiency also have been described in patients who have a familial disorder with predisposition to AML (FPD/AML), indicating the role of AML1 in megakaryopoiesis. Using single-strand conformation polymorphism analysis, we studied the AML1 runt domain in 41 patients with M0 AML and identified potentially pathologic mutations in five (12%). Biallelic disease could be confirmed in only one patient, using loss of heterozygosity studies. At least three of the mutations would lead to truncated proteins similar to those reported in FPD/AML, suggesting that haploinsufficiency plays a role in the pathogenesis of this minimally differentiated type of leukemia. The incidence of acquired mutations in AML patients with acute megakaryoblastic leukemia (FAB type M7) was the same as that reported in other non-M0 patients, with only one mutation detected in 20 (5%) patients studied.

Adult↗
PubMed2002

Basic sciences of the myeloproliferative diseases: pathogenic mechanisms of ET and PV.

The molecular pathogenesis of ET and PV is unknown, although the relatively indolent clinical course observed in most patients suggests that the defect may be subtle and difficult to establish. Clonality analysis using X-chromosome inactivation patterns in females on purified CD34+ cells have confirmed that a defect is present in the hematopoietic stem cell. However, at least in ET, a significant proportion of patients have polyclonal hemopoiesis, and this presumably reflects the heterogeneous nature of the disorder(s). Attention has focussed on the potential disruption of the physiological regulators EPO and TPO and their respective receptors. In familial disorders, pathological mutations have been identified in some, but by no means all, cases: EPO receptor mutations in PFCP, TPO mutations in FT and, conversely, TPO receptor (c-mpl) mutations in CAMT. Equivalent ligand or receptor mutations have not been detected in ET or PV patients. However, there is evidence to suggest that c-mpl expression may be dysregulated, with low or absent c-mpl mRNA or protein reported in ET and/or PV patients. At present it is not clear whether this is the cause or consequence of the paradoxically normal/increased TPO levels found with both primary and secondary thrombocytosis. In vitro culture analysis has demonstrated both cytokine independence and hyper-sensitivity as a generalised feature of progenitor cells from many patients, but differences exist depending on the assays used and there is little understanding of the mechanism(s) underlying these responses. Two genes have recently been identified with increased mRNA expression in PV granulocytes: PRV-1, a novel cell surface receptor closely related to the uPAR/Ly6/CD59/snake toxin family of proteins, and NFI-B, a member of the nuclear factor I family which may be associated with TGF-beta resistance. Investigation of their regulation and biological effects may assist in determining the pathobiology of these elusive disorders.

Cytokines↗