Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes

Asimakopoulos, Fotios A.; White, Nicholas J.; Holloway, Tracey; Nacheva, Elisabeth P.; Green, Anthony

doi:10.1016/0145-2126(94)90218-6

Cited by 30 publications

(41 citation statements)

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“…58 In addition, patients have been observed where all hematopoietic cells had deletions of 20q loss and only a subset were positive for JAK2V617F. 59 These data suggest there are 'pre-JAK2 alleles' which arise before the acquisition of the JAK2V617F allele in some patients.…”

Section: Additional Somatic Mutationsmentioning

confidence: 97%

JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

2008

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Although it has long been known that the myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic stem-cell disorders, for many years the genetic basis for these disorders was elusive. A new era in MPN biology began in 2005 with the discovery of a somatic point mutation in JAK2 tyrosine kinase (JAK2V617F), which was identified in a significant proportion of patients with PV, ET and PMF. Based on the hypothesis that JAK-STAT signaling is central to the pathogenesis of JAK2V617F-negative MPN, genomic studies have identified JAK2 exon 12 mutations in JAK2V617F-negative PV and activating mutations in MPL in patients with JAK2V617F-negative ET and PMF. In this review, we will discuss the role of these mutant alleles in the pathogenesis of PV, ET and PMF, the potential therapeutic implications of these discoveries, and the implications of these discoveries for genomic studies of hematopoietic malignancies.

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Section: Additional Somatic Mutationsmentioning

confidence: 97%

JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

2008

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“…FISH mapping was performed using the dual colour/dual probe approach as previously described (Asimakopoulos et al, 1996b;Nacheva et al, 1995a) with one probe being a PAC derived from the centromeric region of chromosome 20 (CEP20). PACs which mapped to the long arm of chromosome 20 were identi®ed from the PAC/BAC contig or obtained from Vysis (LSI D20S108 and LSI 20q13).…”

Section: Fish Mappingmentioning

confidence: 99%

Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes

et al. 2000

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“…The clinical details of the patients are shown in Table 1. Granulocyte DNA was studied since peripheral blood granulocytes have been previously shown to arise from the transformed progenitor in patients with PV (Asimakopoulos et al, 1994(Asimakopoulos et al, , 1996 and references therein). These cells may carry cytogenetic abnormalities detectable in bone marrow of patients with this disorder and several reports have demonstrated that granulocytes but not lymphocytes demonstrate unilateral X-inactivation patterns in patients with PV.…”

Section: Peripheral Blood Granulocytes Are Clonal and T Cells Polyclomentioning

confidence: 99%

“…The probe was a full length SHP-1 cDNA clone (Plutzky et al, 1992). A probe from the short arm of chromosome 20 (p4.8) was used for control hybridisations (Asimakopoulos et al, 1994). Membranes were washed at high stringency (0.26SSC, 0.1% SDS, 2615 min at room temperature, 1615 min at 65 ± 688C) and exposed to autoradiographic ®lm.…”

Section: Dna Extraction and Quantitative Southern Blotting Analysismentioning

confidence: 99%

The gene encoding hematopoietic cell phosphatase (SHP-1) is structurally and transcriptionally intact in polycythemia vera

et al. 1997

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Polycythemia vera (PV) is an acquired clonal disorder characterized by increased production of mature red cells and growth of erythroid colonies in the absence of erythropoietin. Mutation of the erythropoietin receptor has been demonstrated to cause familial polycythemia, but no mutations have been found in PV. Moreover, both erythroid and myeloid progenitors from patients with PV have been reported to be hypersensitive to a number of dierent growth factors. Attention has therefore focused on post-receptor signal transduction pathways. The SHP-1 gene is an especially attractive candidate gene. Firstly, SHP-1 binds to and negatively regulates signalling from the erythropoietin receptor and is likely to regulate other cytokine receptors in a similar manner. Secondly, absence of SHP-1 protein in the motheaten mouse is accompanied by increased sensitivity of hematopoietic progenitors to a number of cytokines including erythropoietin. Thirdly, familial or sporadic polycythemia in man may result from mutations of the SHP-1 binding domain of the erythropoietin receptor. We have therefore searched for mutations of the SHP-1 gene in genomic DNA from patients with PV. In this disease the majority of peripheral blood lymphocytes are not part of the malignant clone and a variable proportion of myeloid cells may arise from normal progenitors. We have therefore chosen to study DNA from puri®ed peripheral blood granulocytes obtained from nine women in whom the granulocytes were clonally derived. Southern analysis was used to show that the gene was not rearranged and densitometry con®rmed the presence of two copies of the gene in each DNA sample. Sequencing of the entire coding region and all splice junctions revealed no mutations. Hematopoietic transcription factor binding sites in the SHP-1 promoter region were intact and the methylation status of the two SHP-1 promoters in PV patients was identical to that in three normal controls. Finally, we showed that levels of SHP-1 protein in granulocytes from patients was similar to those from normal controls. These results demonstrate that the SHP-1 gene is structurally and transcriptionally intact in patients with PV.

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Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes

Cited by 30 publications

References 0 publications

JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science

Chromosome 20 deletions in myeloid malignancies: reduction of the common deleted region, generation of a PAC/BAC contig and identification of candidate genes

The gene encoding hematopoietic cell phosphatase (SHP-1) is structurally and transcriptionally intact in polycythemia vera

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