Grant Number:	2R01CA105312-05 Interpret this number
Primary Investigator:	Bessler, Monica
Organization:	Washington University
Project Title:	Molecular Studies of Bone Marrow Failure
Fiscal Year:	2010

DESCRIPTION (provided by applicant): The overall goal of our research is to improve the diagnosis, care, and treatment of patients with bone marrow failure (BMF). One focus of our research is dyskeratosis congenita (DC), a rare inherited form of BMF associated with a classic triad of mucocutaneous features including abnormal pigmentation, dystrophic nail changes, and leukoplakia of the oral mucosa. Mutations in 6 different genes, all involved in the maintenance of telomeres, have been identified in patients with DC. During our last funding period we investigated the frequency, heritability, penetrance, and expressivity of mutations in TERC and in the telomerase catalytic subunit TERT in patients diagnosed with BMF and their families. Our studies identified small but distinctive populations of patients with BMF due to TERC or TERT gene mutations. Disease penetrance and expressivity were highly variable depending on the gene mutated, the nature of the mutation, and the number of generations the mutation had been inherited. Among patients with BMF the measurement of short telomeres in peripheral blood cells was found to be a sensitive though nonspecific method for identifying patients with DC. Our studies and those of other investigators have shown that patients with the classic clinical features of DC are only the "tip of the iceberg" of individuals who have BMF due to defective telomere maintenance. Because of these discoveries there is confusion and disagreement about the clinical significance of short telomeres and mutations in telomere maintenance genes. We hypothesize that premature senescence of hematopoietic stem cells is the basis of BMF in patients with DC and that the major cause of premature senescence is dysfunctional telomeres. In the proposed research we will longitudinally monitor telomere length in patients with BMF and mutations in DC associated genes and determine whether the rate of telomere shortening or telomere length correlates with the severity of BMF. We will investigate the functional consequences of newly identified sequence alterations in DC associated genes on telomerase activity at the telomere end and investigate the pathways that lead to short telomeres and premature senescence in primary cells from patients with the disease. We will test whether an increase in telomerase activity and/or antioxidants will delay the onset of senescence in the mutant cells. These proof-of-principle experiments may identify new treatment options for patients with DC and possibly other related conditions associated with BMF and cancer predisposition. PUBLIC HEALTH RELEVANCE: The bone marrow produces blood cells that serve to fight infections, stop bleeding, and transport oxygen to tissues. Patients with inherited bone marrow failure syndromes (IBMFS) are unable to make sufficient numbers of blood cells, resulting in major disability and early death. Some of these patients have mutations in critical genes that determine the length and integrity of the chromosome end, known as the telomere. Classically these patients present with additional clinical manifestations, including alterations of the skin, white spots on the tongue and brittle fingernails, which led to the disease name, dyskeratosis congenita (DC). Our work and that of others has shown that mutations in these DC associated genes are much more frequent than originally presumed and that the majority of patients do not present with the classic associated manifestations. However, at the time of bone marrow failure (BMF) all patients with DC have short telomeres. There are multiple mechanisms that shorten the telomeres. They all cause cells to stop growing and to age prematurely. The proposed research will characterize the mechanisms that lead to short telomeres in patients with DC and test whether the inhibition of these mechanisms will improve cell growth and prevent or delay premature aging of these cells. These experiments will hopefully identify new treatments for patients with DC and possibly also for patients with other types of BMF.




Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype.
Authors: Sarthy J. , Zha J. , Babushok D. , Shenoy A. , Fan J.M. , Wertheim G. , Himebauch A. , Munchel A. , Taraseviciute A. , Yang S. , et al. .
Source: Blood Advances, 2018-01-23 00:00:00.0; 2(2), p. 120-125.
PMID: 29365320
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Somatic HLA Mutations Expose the Role of Class I-Mediated Autoimmunity in Aplastic Anemia and its Clonal Complications.
Authors: Babushok D.V. , Duke J.L. , Xie H.M. , Stanley N. , Atienza J. , Perdigones N. , Nicholas P. , Ferriola D. , Li Y. , Huang H. , et al. .
Source: Blood Advances, 2017-10-10 00:00:00.0; 1(22), p. 1900-1910.
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Clonal Replacement Underlies Spontaneous Remission In Paroxysmal Nocturnal Haemoglobinuria
Authors: Babushok D.V. , Stanley N. , Xie H.M. , Huang H. , Bagg A. , Olson T.S. , Bessler M. .
Source: British Journal Of Haematology, 2017 Feb; 176(3), p. 487-490.
PMID: 26913981
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Recent Advances In Understanding Clonal Haematopoiesis In Aplastic Anaemia
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Source: British Journal Of Haematology, 2017-01-20 00:00:00.0; , .
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Clonal hematopoiesis in patients with dyskeratosis congenita.
Authors: Perdigones N. , Perin J.C. , Schiano I. , Nicholas P. , Biegel J.A. , Mason P.J. , Babushok D.V. , Bessler M. .
Source: American Journal Of Hematology, 2016 Dec; 91(12), p. 1227-1233.
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Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres.
Authors: Babushok D.V. , Grignon A.L. , Li Y. , Atienza J. , Xie H.M. , Lam H.S. , Hartung H. , Bessler M. , Olson T.S. .
Source: American Journal Of Hematology, 2016 Feb; 91(2), p. 243-7.
PMID: 26615915
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Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults.
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Source: Leukemia & Lymphoma, 2016; 57(3), p. 520-36.
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Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.
Authors: Betensky M. , Babushok D. , Roth J.J. , Mason P.J. , Biegel J.A. , Busse T.M. , Li Y. , Lind C. , Papazoglou A. , Monos D. , et al. .
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Hepatitis B virus reactivation after withdrawal of prophylactic antiviral therapy in patients with diffuse large B cell lymphoma.
Authors: Liu W.P. , Wang X.P. , Zheng W. , Ping L.Y. , Zhang C. , Wang G.Q. , Song Y.Q. , Zhu J. .
Source: Leukemia & Lymphoma, 2016; 57(6), p. 1355-62.
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Mice with a Mutation in the Mdm2 Gene That Interferes with MDM2/Ribosomal Protein Binding Develop a Defect in Erythropoiesis.
Authors: Kamio T. , Gu B.W. , Olson T.S. , Zhang Y. , Mason P.J. , Bessler M. .
Source: Plos One, 2016; 11(4), p. e0152263.
PMID: 27042854
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Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
Authors: Babushok D.V. , Olson T.S. , Bessler M. .
Source: The New England Journal Of Medicine, 2015-10-22 00:00:00.0; 373(17), p. 1673.
PMID: 26488703
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Variations in reactive oxygen species between mouse strains.
Authors: Reeves D.A. , Gu B.W. , Bessler M. , Mason P.J. .
Source: Blood Cells, Molecules & Diseases, 2015 Oct; 55(3), p. 189-90.
PMID: 26227841
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mRNA deadenylation and telomere disease.
Authors: Mason P.J. , Bessler M. .
Source: The Journal Of Clinical Investigation, 2015 May; 125(5), p. 1796-8.
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Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.
Authors: Babushok D.V. , Perdigones N. , Perin J.C. , Olson T.S. , Ye W. , Roth J.J. , Lind C. , Cattier C. , Li Y. , Hartung H. , et al. .
Source: Cancer Genetics, 2015 Apr; 208(4), p. 115-28.
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Genetic predisposition syndromes: when should they be considered in the work-up of MDS?
Authors: Babushok D.V. , Bessler M. .
Source: Best Practice & Research. Clinical Haematology, 2015 Mar; 28(1), p. 55-68.
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Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients.
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Source: Plos One, 2015; 10(5), p. e0127414.
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Dysregulation of the Transforming Growth Factor ß Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia.
Authors: Ge J. , Apicella M. , Mills J.A. , Garçon L. , French D.L. , Weiss M.J. , Bessler M. , Mason P.J. .
Source: Plos One, 2015; 10(8), p. e0134878.
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Inherited bone marrow failure syndromes in adolescents and young adults.
Authors: Wilson D.B. , Link D.C. , Mason P.J. , Bessler M. .
Source: Annals Of Medicine, 2014 Sep; 46(6), p. 353-63.
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Liver failure due to hepatic angiosarcoma in an adolescent with dyskeratosis congenita.
Authors: Olson T.S. , Chan E.S. , Paessler M.E. , Sullivan K.E. , Frantz C.N. , Russo P. , Bessler M. .
Source: Journal Of Pediatric Hematology/oncology, 2014 May; 36(4), p. 312-5.
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Single nucleotide polymorphism array analysis of bone marrow failure patients reveals characteristic patterns of genetic changes.
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Source: British Journal Of Haematology, 2014 Jan; 164(1), p. 73-82.
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Case Report: Paroxysmal nocturnal hemoglobinuria in a woman heterozygous for G6PD A-.
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Source: F1000research, 2014; 3, p. 194.
EPub date: 2014-08-13 00:00:00.0.
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Using induced human pluripotent stem cells to study Diamond-Blackfan anemia: an outlook on the clinical possibilities.
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Acquired aplastic anemia in children.
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Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients.
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Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin.
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A family with Hoyeraal-Hreidarsson syndrome and four variants in two genes of the telomerase core complex.
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Source: British Journal Of Haematology, 2012 Nov; 159(4), p. 480-2.
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Recent insights into inherited bone marrow failure syndromes.
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Source: Current Opinion In Pediatrics, 2012 Feb; 24(1), p. 23-32.
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The role of HMGA2 in the proliferation and expansion of a hematopoietic cell in myeloproliferative neoplasms.
Authors: Ikeda K. , Ogawa K. , Takeishi Y. .
Source: Fukushima Journal Of Medical Science, 2012; 58(2), p. 91-100.
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The genetics of dyskeratosis congenita.
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3'UTR-truncated Hmga2 cDNA causes MPN-like hematopoiesis by conferring a clonal growth advantage at the level of HSC in mice.
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Source: Blood, 2011-06-02 00:00:00.0; 117(22), p. 5860-9.
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Accelerated hematopoietic stem cell aging in a mouse model of dyskeratosis congenita responds to antioxidant treatment.
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Source: Aging Cell, 2011 Apr; 10(2), p. 338-48.
PMID: 21241452
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Cytokinesis failure and attenuation: new findings in Fanconi anemia.
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Source: The Journal Of Clinical Investigation, 2011 Jan; 121(1), p. 27-30.
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Dyskeratosis congenita.
Authors: Bessler M. , Wilson D.B. , Mason P.J. .
Source: Febs Letters, 2010-09-10 00:00:00.0; 584(17), p. 3831-8.
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Acquired monosomy 7 myelodysplastic syndrome in a child with clinical features suggestive of dyskeratosis congenita and IMAGe association.
Authors: McDonald S. , Wilson D.B. , Pumbo E. , Kulkarni S. , Mason P.J. , Else T. , Bessler M. , Ferkol T. , Shenoy S. .
Source: Pediatric Blood & Cancer, 2010 Jan; 54(1), p. 154-7.
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Dyskerin ablation in mouse liver inhibits rRNA processing and cell division.
Authors: Ge J. , Rudnick D.A. , He J. , Crimmins D.L. , Ladenson J.H. , Bessler M. , Mason P.J. .
Source: Molecular And Cellular Biology, 2010 Jan; 30(2), p. 413-22.
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TINF2 mutations in children with severe aplastic anemia.
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Source: Pediatric Blood & Cancer, 2009 May; 52(5), p. 687.
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TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements.
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Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.
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Telomerase reverse transcriptase haploinsufficiency and telomere length in individuals with 5p- syndrome.
Authors: Du H.Y. , Idol R. , Robledo S. , Ivanovich J. , An P. , Londono-Vallejo A. , Wilson D.B. , Mason P.J. , Bessler M. .
Source: Aging Cell, 2007 Oct; 6(5), p. 689-97.
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Dysfunctional telomeres and dyskeratosis congenita.
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Source: Haematologica, 2007 Aug; 92(8), p. 1009-12.
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A four base pair insertion in exon 1 of the RPS19 gene is a common polymorphism in African-Americans.
Authors: Huang Q. , Robledo S. , Wilson D.B. , Bessler M. , Mason P.J. .
Source: British Journal Of Haematology, 2006 Dec; 135(5), p. 745-6.
PMID: 17107358
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Immunosuppressive therapy for acute porphyria: safety and efficacy in a patient with bone marrow failure.
Authors: Field J.J. , Giannone L. , Bessler M. , Blinder M.A. .
Source: Pharmacotherapy, 2006 Nov; 26(11), p. 1662-6.
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Low frequency of telomerase RNA mutations among children with aplastic anemia or myelodysplastic syndrome.
Authors: Field J.J. , Mason P.J. , An P. , Kasai Y. , McLellan M. , Jaeger S. , Barnes Y.J. , King A.A. , Bessler M. , Wilson D.B. .
Source: Journal Of Pediatric Hematology/oncology, 2006 Jul; 28(7), p. 450-3.
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The effect of TERC haploinsufficiency on the inheritance of telomere length.
Authors: Goldman F. , Bouarich R. , Kulkarni S. , Freeman S. , Du H.Y. , Harrington L. , Mason P.J. , Londoño-Vallejo A. , Bessler M. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2005-11-22 00:00:00.0; 102(47), p. 17119-24.
EPub date: 2005-11-22 00:00:00.0.
PMID: 16284252
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