From 10 to 20% of acquired aplastic anemia survivors will develop a clonal disease within the decade following their diagnosis as will up to 40% of children and young adults with the inherited bone marrow failure syndrome Fanconi anemia. Recent work from the laboratories of the applicants and from other centers leads to the conclusion that clonal evolution in aplastic states arises in the context of ongoing stem cell damage through a process of clonal selection and adaptation. In the past year the two applicants have each independently developed a unique murine model of clonal evolution in Fanconi anemia. The applicants propose herein to use these models to identify the earliest molecular events involved in clonal evolution of FA stem cells. These models provided material for genome wide expression analyses which, when combined with our recently completed studies on the human bone marrow transcriptome, have not only confirmed the adaptive nature of clonal selection in this disease but have yielded common candidate genes, the potential of one of which (HoxA9) to facilitate clonal selection of adapted cells has been established in preliminary studies. A second family of genes has potential to explain the molecular underpinnings of the random aneuploidy that is characteristic of MDS in FA. Collectively, our goals are to identify genetic and epigenetic causes of clonal evolution in vitro and in vivo. We anticipate that by doing so, we can use the knowledge to develop strategies for prevention of clonal evolution in patients at high risk. We will use murine and human FA cells that have not undergone clonal evolution (FAAPL) and FA cells that have clonally evolved (FACL).

Public Health Relevance

This application seeks to identify molecular mechanisms that underlie the development of myeloid malignancies and aplastic anemia. Information learned from this application may provide insights into the treatment of myelodys plasia and acute myelogenous leukemia. These are hematopoietic malignances that are important in adults and particularly the elderly as well as in children with a genetic disorder called Fanconi Anemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA138237-05
Application #
8302374
Study Section
Special Emphasis Panel (ZCA1-GRB-I (O3))
Program Officer
Mufson, R Allan
Project Start
2008-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$379,440
Indirect Cost
$58,492
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Wiek, Constanze; Schmidt, Eva M; Roellecke, Katharina et al. (2015) Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol. Biochem J 465:103-14
Blue, Emily K; DiGiuseppe, Robert; Derr-Yellin, Ethel et al. (2014) Gestational diabetes induces alterations in the function of neonatal endothelial colony-forming cells. Pediatr Res 75:266-72
Nalepa, Grzegorz; Clapp, D Wade (2014) Fanconi anemia and the cell cycle: new perspectives on aneuploidy. F1000Prime Rep 6:23
Park, J-Y; Singh, T R; Nassar, N et al. (2014) Breast cancer-associated missense mutants of the PALB2 WD40 domain, which directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair. Oncogene 33:4803-12
Scheckenbach, Kathrin; Baldus, Stephan E; Balz, Vera et al. (2014) RAD51C--a new human cancer susceptibility gene for sporadic squamous cell carcinoma of the head and neck (HNSCC). Oral Oncol 50:196-9
Nalepa, Grzegorz; Enzor, Rikki; Sun, Zejin et al. (2013) Fanconi anemia signaling network regulates the spindle assembly checkpoint. J Clin Invest 123:3839-47
Nalepa, Grzegorz; Barnholtz-Sloan, Jill; Enzor, Rikki et al. (2013) The tumor suppressor CDKN3 controls mitosis. J Cell Biol 201:997-1012
Dao, Kim-Hien T; Rotelli, Michael D; Brown, Brieanna R et al. (2013) The PI3K/Akt1 pathway enhances steady-state levels of FANCL. Mol Biol Cell 24:2582-92
Garbati, Michael R; Hays, Laura E; Keeble, Winifred et al. (2013) FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1* in macrophages. Blood 122:3197-205
Scheckenbach, K; Wagenmann, M; Freund, M et al. (2012) Squamous cell carcinomas of the head and neck in Fanconi anemia: risk, prevention, therapy, and the need for guidelines. Klin Padiatr 224:132-8

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