Biomedical subjects

Jacqueline Boultwood

Publications and source records attributed to Jacqueline Boultwood.

5 recordsLinked to original sources

PubMed2003

Gene expression profiling in polycythemia vera using cDNA microarray technology.

Polycythemia vera (PV) is a myeloproliferative disorder characterized by an increased proliferation of all three myeloid lineages. The molecular pathogenesis of PV is unknown. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profile of granulocytes obtained from 11 PV patients compared with granulocytes obtained from healthy individuals. We found that 147 genes were up-regulated by >/==" BORDER="0">2.5 fold in the majority of PV patients. Eleven of these 147 genes were up-regulated in all PV patients studied and may represent a molecular signature for this disorder. An increase in the expression of several protease inhibitors with affinity for proteases that promote apoptosis in neutrophils (e.g., cystatin F, secretory leukocyte protease inhibitor), as well as the up-regulation of a number of antiapoptotic and survival factors was found (e.g., adrenomedullin, p38 mitogen-activated protein kinase). We speculate that the deregulation of these factors may inhibit normal apoptosis and promote cell survival in the granulocytes of patients with PV. These PV-specific expression changes are likely to be biologically important in the pathophysiology of this disorder.

Gene Expression Profiling↗

PubMed2003

Identification of acquired somatic mutations in the gene encoding chromatin-remodeling factor ATRX in the alpha-thalassemia myelodysplasia syndrome (ATMDS).

Inherited mutations of specific genes have elucidated the normal roles of the proteins they encode by relating specific mutations to particular phenotypes. But many potentially informative mutations in such genes are lethal early in development. Consequently, inherited mutations may not reflect all the functional roles of such proteins. Acquired, somatic defects should reflect a wider spectrum of mutations because they are not prone to negative selection in development. It has been difficult to identify such mutations so far, but microarray analysis provides a new opportunity to do so. Using this approach, we have shown that in individuals with myelodysplasia associated with alpha-thalassemia (ATMDS), somatic mutations of the gene encoding the chromatin remodeling factor ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene. These findings cast new light on this pleiotropic cofactor, which appears to be an essential component rather than a mere facilitator of globin gene expression.

Base Sequence↗

PubMed2003

Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.

The BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

Chromosomes, Human, Pair 1↗

PubMed2002

Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome.

The 5q- syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q- syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensembl gene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34(+) cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q- syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.

Antigens, CD34↗

PubMed2001

Clonality in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDSs) comprise a heterogeneous group of stem cell disorders involving cytopenia and dysplastic changes in 3 hematopoietic lineages. Although it is accepted that MDS is a clonal disorder, the exact nature of the involvement of multipotent stem cells and progenitor cells has not been resolved. Most clonality studies of MDS support the proposal that the primary neoplastic event occurs, in most patients, at the level of a committed myeloid progenitor cell, capable of differentiation into multiple myeloid lineages. The extent of the involvement of T and B lymphocytes in MDS remains controversial. Much of the variation reported may result from disease heterogeneity and technical issues such as skewed methylation patterns occurring in studies analyzing X-chromosome inactivation patterns (XCIP) and possible impurities in lymphocyte preparation. A great deal of the evidence in support of T-lymphocyte involvement in MDS has been generated by XCIP studies, and some of these data need to be treated with caution, especially data from studies in which appropriate controls were omitted. In contrast, B-lymphocyte involvement in some patients with MDS is based on studies using more robust technology including combined immunophenotyping and fluorescence in situ hybridization. Clonality studies involving myeloid and lymphoid cells in MDS have yielded discrepant results with regard to the potential involvement of multipotent (lympho-myeloid) hematopoietic stem cells (HSCs). However, failure to detect a clonal marker in all cells of all lineages does not preclude multipotent-HSC involvement. Some recent studies have produced compelling evidence to show that, in some patients with MDS, the multipotent HSC is the target of the primary neoplastic event. It now seems probable that MDS arises in multipotent HSCs more commonly than previously recognized. Such data not only provide important new insights into the biology of MDS but also may have therapeutic implications. The determination of whether multipotent HSCs are involved in the MDS clone may be important for the use of autologous stem cell transplantation in these patients.

Cell Lineage↗