Philip J Mason, Ph.D.

faculty photo
Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

Contact information
The Children's Hospital of Philadelphia
Abramson Research Center
3615 Civic Center Blvd, Room 302E
Philadelphia, PA 19104
Office: 267-426-9327
Fax: 267-426-9892
Education:
B.Sc. (Genetics)
University of Edinburgh, Scotland, 1976.
PhD
University of Edinburgh, Scotland, 1980.
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Description of Research Expertise

Research interests
Molecular biology of telomere maintenance and ribosome biogenesis. The pathogenesis of inherited bone marrow failure syndromes.

Key words
Telomeres, telomerase, ribosome biogenesis, ribosomal proteins, dyskeratosis congenita, Diamond Blackfan Anemia

Research Projects for 2012
1. Telomere maintenance in Mus castaneus mice with Dkc1 mutations.
2. Ribosome biogenesis in iPS cells haploinsufficient for ribosomal proteins.
3. The role of pseudouridylation in ribosome biogenesis and translation.

Description of Research
We are a molecular hematology lab interested in the pathogenesis of bone marrow failure (BMF)syndromes, with particular emphasis on Dyskeratosis Congenita (DC) and Diamond Blackfan Anemia (DBA). Our experiments have led us into investigations of basic biological mechanisms of telomere maintenance, which underlies DC and ribosome biogenesis, which is faulty in DBA. We use mutant mice, induced pluripotent stem cells (iPSCs), tissue culture cells and cells from consented patients in our studies. We are interested in how the mutations in DC and DBA perturb telomere maintenance and ribosome biogenesis and in the mechanisms by which the perturbations cause failure of hematopoiesis. Our studies may be relevant to how both these conditions lead to an increased risk of leukemia and other malignancies. Major projects in the laboratory include:-

1. Development of a mouse model of X-linked dyskeratosis congenita. We have used gene targeting to produce mice containing the mutations in the Dkc1 gene that cause DC in humans. The mice show several key features of the disease including premature aging of hematopoietic stem cells. The premature aging phenotype is largely corrected when the mice are treated with the antioxidant N-acetylcysteine. The role of oxidative stress in the disease is under investigation. We are introducing the mutant gene into a strain of wild mice that have short telomeres to study those effects of the mutations that trigger a critically short telomere response.

2. Testing drugs that may combat bone marrow failure. We have developed a sensitive cell culture system to test the effect of drugs and specific gene manipulation on the growth rate of cells with DC mutations. We are using the system to test a range of anti-oxidants, specific inhibitors and siRNAs to discover which metabolites and signaling molecules can be inhibited to improve the growth of DC cells. In separate experiments we are testing out specific drugs that suppress premature STOP codons for their potential use in patients whose pathogenic mutation causes premature termination.

3. We are trying to find out how ribosomal protein haploinsufficiency, the cause of most cases of DBA leads to failure of erythropoiesis. In cell lines we are knocking down different ribosomal prorteins and monitoring the changes in gene expression and in recruitment of mRNAs into polysomes. In collaboration with Mitch Weiss’s lab we are studying iPSCs made from DBA patients’ cells. These cells show molecular features of DBA and may be useful in characterizing the events that lead to red cell aplasia in this disease.

4. We are investigating clonal hematopiesis in BMF syndromes. Clonal hematopoiesis may be due to an acquired mutation that gives cells a growth advantage at the stem cell of progenitor level. These mutations may lead to remission from the effects of BMF or may lead to the development of a malignant clone. Our aim is to determine the nature of the genomic changes leading to clonality by using SNP arrays and whole exome (or genome) sequencing. This information may be useful in developing new treatments or in the discovery of early markers of malignancy.

Selected Publications

Babushok DV, Xie HM, Roth JJ, Perdigones N, Olson TS, Cockroft JD, Gai X, Perin JC, Li Y, Paessler ME, Hakonarson H, Podsakoff GM, Mason PJ, Biegel JA, Bessler M: Single nucleotide polymorphism array analysis of bone marrow failure patients reveals characteristic patterns of genetic changes. Br J Haematol. Blackwell Publishing, October 2013.

Babushok DV, Li Y, Roth JJ, Perdigones N, Cockroft JD, Biegel JA, Mason PJ, Bessler M: Common polymorphic deletion of gluthathione S-transferase theta predisposes to acquired aplastic anemia: Independent cohort and meta-analysis of 609 patients. Am J Hematol 88(10): 862-867, October 2013.

Garcon L, Ge J, Manjunath SH, Mills A, Apicella M, Parikh S, Sullivan LM, Podsakoff GM, Gadue P, French DL, Mason PJ, Bessler M, Weiss MJ: Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood 122(6): 912-921, August 2013.

Gu BW, Ge J, Fan JM, Bessler M, Mason PJ: Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin. FEBS Lett 587(14): 2112-2117, July 2013.

Vogiatzi P, Perdigones N, Mason PJ, Wilson DB, Bessler M. : A family with Hoyeraal-Hreidarsson syndrome and four variants in two genes of the telomerase core complex. Pediatr Blood Cancer 60(6): E4-6, June 2013.

Mason PJ, Bessler M.: Poikiloderma with neutropenia: beginning at the end. Aberrant 3' oligoadenylation of spliceosomal U6 small nuclear RNA in poikiloderma with neutropenia. Blood 121(6): 872-4, February 2013.

Gu BW, Mason PJ.: Telomere 3' overhang and disease. Leuk Lymphoma February 2013.

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Last updated: 10/30/2013
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