Why do some people get cancer and others do not gets to the heart of cancer biology. Recently, the NCI invited leading cancer investigators to identify provocative questions that will transform our understanding and treatment of cancer. Our application addresses one of these questions: are there definable properties of premalignant lesions that predict the likelihood of progression. This is not just of profound biological importance, but also of great relevance to people with cancer predisposition. Patients with congenital bone marrow failure syndromes (for example, Fanconi anemia, Shwachman-Diamond Syndrome, Severe Congenital Neuropenia, and dyskeratosis congenital) are at greatly increased risk (1000x) for developing life-threatening acute myeloid leukemia/myelodysplastic syndromes (AML/MDS). What are the genetic factors that contribute to disease progression? Can this progression be prevented first by identification of these genetic co-modifiers and then to design preventative measures? This proposal seeks to identify genetic co-modifiers that arise in patients with Shwachman-Diamond Syndrome, one of the more common inherited bone marrow failure syndromes with the risk of AML/MDS. However, two major obstacles block progression: the low prevalence of the disease and the decade long latency period. To overcome these obstacles we are developing an adult zebrafish model of Shwachman-Diamond Syndrome and screen for genetic mutations that result in leukemia. The disease is due to a mutation in the SBDS gene, which encodes a protein involved in ribosomal maturation. We have cloned the highly homologous zebrafish gene, sbds, and its promoter for the sbds gene and have developed tools for controlled expressions of Sbds. Fascinatingly, almost all patients with this syndrome who develop leukemia acquire loss of chromosome 7. This abnormality is also found in a number of pediatric and adult patients with AML/MDS. While there is a minimally deleted region on chromosome 7q, the identity of that tumor suppressor is unknown. We will test several candidate genes in our model system. By identifying genetic co-modifiers and determining how they disturb hematopoiesis, we will be able to eventually design preventative strategies as well as more effective therapies for those who have already developed AML/MDS. In addition, since Shwachman-Diamond Syndrome also causes pancreatic insufficiency, growth retardation, and developmental disabilities, our model will have added value to other biologists and clinicians.

Public Health Relevance

Myelodysplastic Syndromes (MDS) are increasing in incidence due to better diagnosis and an aging population. Better understanding of the pathophysiology of MDS will lead to improved therapies. We will be study Shwachman-Diamond Syndrome, an inherited disorder that results in MDS or AML in up to 40%. We will develop a novel zebrafish model for Shwachman-Diamond Syndrome and validate its ability to develop leukemia by crossing the zebrafish with known and predicted genetic cofactors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21CA159203-03
Application #
9308169
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O2))
Program Officer
Mufson, R Allan
Project Start
2014-01-01
Project End
2016-03-31
Budget Start
2015-11-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$27,567
Indirect Cost
$9,490
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Corey, Seth J; Oyarbide, Usua (2017) New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing. Hematology Am Soc Hematol Educ Program 2017:172-180
Austin, Frances; Oyarbide, Usua; Massey, Gita et al. (2017) Synonymous mutation in TP53 results in a cryptic splice site affecting its DNA-binding site in an adolescent with two primary sarcomas. Pediatr Blood Cancer 64:
Pezeshki, Alex; Podder, Shreya; Kamel, Ralph et al. (2017) Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review. Pediatr Blood Cancer 64:
Mehta, Hrishikesh M; Malandra, Michael; Corey, Seth J (2015) G-CSF and GM-CSF in Neutropenia. J Immunol 195:1341-9
Mehta, Hrishikesh M; Corey, Seth J (2014) Linking stress granulopoiesis to protein synthesis through GADD34. Immunol Cell Biol 92:102-4
Corey, Seth Joel; Kimmel, Marek; Leonard, Joshua N (2014) Systems hematology: an introduction. Adv Exp Med Biol 844:3-10
Mehta, Hrishikesh M; Glaubach, Taly; Corey, Seth Joel (2014) Systems approach to phagocyte production and activation: neutrophils and monocytes. Adv Exp Med Biol 844:99-113
Mehta, H M; Futami, M; Glaubach, T et al. (2014) Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition. Leukemia 28:1041-51
Blatt, Julie; Farag, Sherif; Corey, Seth J et al. (2014) Expanding the scope of drug repurposing in pediatrics: the Children's Pharmacy Collaborative. Drug Discov Today 19:1696-1698
Glaubach, Taly; Minella, Alex C; Corey, Seth J (2014) Cellular stress pathways in pediatric bone marrow failure syndromes: many roads lead to neutropenia. Pediatr Res 75:189-95

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