This site has information on SDS including the common cytogenetic findings in SDS, telomeres, and information on P53 protein overexpression. http://atlasgeneticsoncology.org/Kprones/ShwachmanID10058.html
For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America
Showing posts with label p53 protein. Show all posts
Showing posts with label p53 protein. Show all posts
Sunday, November 2, 2008
Sunday, September 14, 2008
p53 Protein
p53 protein overexpression in Shwachman-Diamond syndrome / In reply
Archives of Pathology & Laboratory Medicine, Oct 2002 by Dror, Yigal, Elghetany, M Tarek, Alter, Blanche P
To the Editor.-We read with great interest the paper of Drs Elghetany and Alter in the April 2002 issue of the ARCHIVES.1 Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystemic disorder characterized by varying degrees of marrow failure and a high propensity for malignant myeloid transformation into myelodysplastic syndromes (MDS) and acute myeloid leukemia.2-4 The authors found p53 overexpression in bone marrow biopsies from 9 patients with SDS. None of the bone marrow biopsies from patients with acquired aplastic anemia or acquired cytopenias and none of those from individuals in the control group had overexpression of p53 protein. Very interestingly, p53 overexpression in patients with SDS was comparable to p53 results in 46 bone marrow specimens from patients with refractory anemia. Refractory anemia is a subtype of MDS.
Although neither the method for selecting patients nor the clinical phenotype of the patients was specified in the paper, the authors' work is important and furthers our understanding of the relationship between SDS and MDS. Myelodysplastic syndrome is a preleukemic, stem cell disease with peripheral blood cytopenia, ineffective hematopoiesis, and varying degrees of bone marrow cellularity and dysplasia. Shwachman-Diamond syndrome meets many of these criteria2: it is a stem cell disorder with peripheral cytopenia, ineffective hematopoiesis,5,6 and varying degrees of bone marrow cellularity, and it carries a significantly increased risk of leukemia.2-4 In addition, scattered mild dysplastic changes in the erythroid, myeloid, and megakaryocytic precursors are commonly seen on careful examination of bone marrow biopsies of patients with SDS2 and are part of the syndrome. Further, the close relationship between SDS and MDS is reflected by similar defects in marrow stromal support of normal hematopoiesis,5 increased apoptosis mediated through the Fas pathway,6 a high frequency of clonal marrow cytogenetic abnormalities,2 and as the authors showed also by a prevalence of p53 protein overexpression that is similar to that in patients with refractory anemia.1 Therefore, SDS seems to be a myelodysplastic disorder from its inception. We therefore consider SDS to be refractory anemia 2 or refractory cytopenia according to the CCC (category-cytology-- cytogenetics) classification of childhood MDS.7 When we refer to malignant myeloid transformation in SDS, we mean stages beyond refractory anemia, namely refractory cytopenia with cytogenetic abnormality, refractory anemia with ring sideroblasts, refractory anemia with dysplasia, refractory cytopenia with excess blasts, or leukemia.
We have recently analyzed bone marrow mononuclear cells from 11 patients with SDS (2 had a clonal marrow cytogenetic abnormality), and we did not find mutations in exons 2 through 11 of the p53 gene.2 Therefore, p53 protein overexpression in SDS can result from either upregulation of the functional p53 gene (as the authors postulated) or posttranslational modification of the protein, rendering it more stable than the wild type protein, which normally cannot be detected.
YIGAL DROR, MD
Marrow Failure and Myelodysplasia Programme
Division of Hematology/ Oncology
The Hospital for Sick Children and the University of Toronto
Toronto, Ontario, Canada M5G 1X8
1. Elghetany MT, Alter BP. p53 Protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126:452-455.
2. Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30:659-669.
3. Mack DR, Forstner GG, Wilschanik M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:15931602.
4. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br] Haematol. 1996;94: 279-284.
5. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999;94:3048-3054.
6. Dror Y, Freedman MH. Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood. 2001;97:3011-3016.
7. Mandel K, Dror Y, Poon A, Freedman MH. Practical classification of pediatric MDS. J Pediatr Hematol Oncol. 2002;24:343-352.
In Reply.-We thank Dr Dror for his comments in support of our recent article.1 Our patients were unselected, and included all of those whose samples were available between November 1999 and November 2000. None of the patients with Shwachman-Diamond syndrome (SDS) had cytogenetic clones, and their bone marrow morphology did not show significant dysplastic features. Thus, p53 overexpression was the hallmark of the similarity between SDS and refractory anemia (RA). Dr Dror raises the interesting question regarding the relationship between this syndrome and RA. Although we agree with Dr Dror that SDS shares common features with RA, it may not be appropriate to classify all patients with this syndrome as having RA at the time of diagnosis. Other bone marrow failure syndromes, such as Fanconi anemia and Diamond-Blackfan anemia, share some features with RA as well.2,3 We are concerned that labeling SDS as RA may prompt an aggressive mode of treatment that may not be supported by data other than these similarities. Moreover, there are some indications that myelodysplastic syndromes evolving from an inherited bone marrow disease may not have the same biological behavior as primary myelodysplastic syndromes in children.4 Longterm prospective studies and the continued search for an underlying molecular defect for SDS should shed some light on this rare disease and its relationship to RA.
For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America
Archives of Pathology & Laboratory Medicine, Oct 2002 by Dror, Yigal, Elghetany, M Tarek, Alter, Blanche P
To the Editor.-We read with great interest the paper of Drs Elghetany and Alter in the April 2002 issue of the ARCHIVES.1 Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystemic disorder characterized by varying degrees of marrow failure and a high propensity for malignant myeloid transformation into myelodysplastic syndromes (MDS) and acute myeloid leukemia.2-4 The authors found p53 overexpression in bone marrow biopsies from 9 patients with SDS. None of the bone marrow biopsies from patients with acquired aplastic anemia or acquired cytopenias and none of those from individuals in the control group had overexpression of p53 protein. Very interestingly, p53 overexpression in patients with SDS was comparable to p53 results in 46 bone marrow specimens from patients with refractory anemia. Refractory anemia is a subtype of MDS.
Although neither the method for selecting patients nor the clinical phenotype of the patients was specified in the paper, the authors' work is important and furthers our understanding of the relationship between SDS and MDS. Myelodysplastic syndrome is a preleukemic, stem cell disease with peripheral blood cytopenia, ineffective hematopoiesis, and varying degrees of bone marrow cellularity and dysplasia. Shwachman-Diamond syndrome meets many of these criteria2: it is a stem cell disorder with peripheral cytopenia, ineffective hematopoiesis,5,6 and varying degrees of bone marrow cellularity, and it carries a significantly increased risk of leukemia.2-4 In addition, scattered mild dysplastic changes in the erythroid, myeloid, and megakaryocytic precursors are commonly seen on careful examination of bone marrow biopsies of patients with SDS2 and are part of the syndrome. Further, the close relationship between SDS and MDS is reflected by similar defects in marrow stromal support of normal hematopoiesis,5 increased apoptosis mediated through the Fas pathway,6 a high frequency of clonal marrow cytogenetic abnormalities,2 and as the authors showed also by a prevalence of p53 protein overexpression that is similar to that in patients with refractory anemia.1 Therefore, SDS seems to be a myelodysplastic disorder from its inception. We therefore consider SDS to be refractory anemia 2 or refractory cytopenia according to the CCC (category-cytology-- cytogenetics) classification of childhood MDS.7 When we refer to malignant myeloid transformation in SDS, we mean stages beyond refractory anemia, namely refractory cytopenia with cytogenetic abnormality, refractory anemia with ring sideroblasts, refractory anemia with dysplasia, refractory cytopenia with excess blasts, or leukemia.
We have recently analyzed bone marrow mononuclear cells from 11 patients with SDS (2 had a clonal marrow cytogenetic abnormality), and we did not find mutations in exons 2 through 11 of the p53 gene.2 Therefore, p53 protein overexpression in SDS can result from either upregulation of the functional p53 gene (as the authors postulated) or posttranslational modification of the protein, rendering it more stable than the wild type protein, which normally cannot be detected.
YIGAL DROR, MD
Marrow Failure and Myelodysplasia Programme
Division of Hematology/ Oncology
The Hospital for Sick Children and the University of Toronto
Toronto, Ontario, Canada M5G 1X8
1. Elghetany MT, Alter BP. p53 Protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. Arch Pathol Lab Med. 2002;126:452-455.
2. Dror Y, Durie P, Ginzberg H, et al. Clonal evolution in marrows of patients with Shwachman-Diamond syndrome: a prospective 5-year follow-up study. Exp Hematol. 2002;30:659-669.
3. Mack DR, Forstner GG, Wilschanik M, Freedman MH, Durie PR. Shwachman syndrome: exocrine pancreatic dysfunction and variable phenotypic expression. Gastroenterology. 1996;111:15931602.
4. Smith OP, Hann IM, Chessells JM, Reeves BR, Milla P. Haematological abnormalities in Shwachman-Diamond syndrome. Br] Haematol. 1996;94: 279-284.
5. Dror Y, Freedman MH. Shwachman-Diamond syndrome: an inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. Blood 1999;94:3048-3054.
6. Dror Y, Freedman MH. Shwachman-Diamond syndrome marrow cells show abnormally increased apoptosis mediated through the Fas pathway. Blood. 2001;97:3011-3016.
7. Mandel K, Dror Y, Poon A, Freedman MH. Practical classification of pediatric MDS. J Pediatr Hematol Oncol. 2002;24:343-352.
In Reply.-We thank Dr Dror for his comments in support of our recent article.1 Our patients were unselected, and included all of those whose samples were available between November 1999 and November 2000. None of the patients with Shwachman-Diamond syndrome (SDS) had cytogenetic clones, and their bone marrow morphology did not show significant dysplastic features. Thus, p53 overexpression was the hallmark of the similarity between SDS and refractory anemia (RA). Dr Dror raises the interesting question regarding the relationship between this syndrome and RA. Although we agree with Dr Dror that SDS shares common features with RA, it may not be appropriate to classify all patients with this syndrome as having RA at the time of diagnosis. Other bone marrow failure syndromes, such as Fanconi anemia and Diamond-Blackfan anemia, share some features with RA as well.2,3 We are concerned that labeling SDS as RA may prompt an aggressive mode of treatment that may not be supported by data other than these similarities. Moreover, there are some indications that myelodysplastic syndromes evolving from an inherited bone marrow disease may not have the same biological behavior as primary myelodysplastic syndromes in children.4 Longterm prospective studies and the continued search for an underlying molecular defect for SDS should shed some light on this rare disease and its relationship to RA.
For information on Shwachman-Diamond Syndrome check out Shwachman-Diamond America
Friday, February 22, 2008
p53 tumor suppressor protein
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107
Genes and Disease Cancers
The p53 tumor suppressor protein
The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.
The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.
Help with unraveling the molecular mechanisms of cancerous growth has come from the use of mice as models for human cancer, in which powerful 'gene knockout' techniques can be used. The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.
Genes and Disease Cancers
The p53 tumor suppressor protein
The p53 gene like the Rb gene, is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.
The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.
Help with unraveling the molecular mechanisms of cancerous growth has come from the use of mice as models for human cancer, in which powerful 'gene knockout' techniques can be used. The amount of information that exists on all aspects of p53 normal function and mutant expression in human cancers is now vast, reflecting its key role in the pathogenesis of human cancers. It is clear that p53 is just one component of a network of events that culminate in tumor formation.
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