This K08 Career Development Award proposal describes the candidate's 5-year training program to become an independent physician-scientist in academic Hematology, with a focus on bone marrow failure (BMF) syndromes. The Principal Investigator (PI) has completed M.D. and Ph.D. Degrees at the University of Pennsylvania (Penn), followed by residency training in Internal Medicine at the Massachusetts General Hospital, fellowship training in Hematology-Oncology at Penn, and has been appointed an Instructor starting July 1, 2015. Through this 5-year career development plan, the PI will expand her knowledge and research skills in hematopoiesis and stem cell biology in order to develop an independent research program studying clonal hematopoiesis in acquired aplastic anemia (aAA). This proposal takes advantage of a large, well-annotated aAA patient registry at the Penn/CHOP Comprehensive Bone Marrow Failure Center. Co-Mentors Dr. Peter Klein and Dr. John Maris, experts on hematopoiesis and translational genomic research, respectively, as well as the Advisory Committee composed of three highly regarded physician-scientists and translational researchers- Dr. Charles Abrams, Dr. Monica Bessler, and Dr. Elizabeth Hexner will mentor the PI's scientific and career development. The proposed research focuses on aAA, a life-threatening blood disease, affecting children and adults, caused by immune destruction of early hematopoietic cells. Clonal evolution to leukemia is a common complication, with no effective prevention strategy available. Emerging data indicate that up to a quarter of aAA patients acquire somatic mutations, and may be at a greater risk of malignant transformation. Therefore, understanding clonal hematopoiesis in aAA is important to allow for early detection and improved therapies. The objective of this proposal is to characterize the full spectrum of clonal hematopoiesis in aAA and to dissect the mechanisms driving emergence of clones.
Specific Aims of this application are: 1) Characterize the landscape and prevalence of somatic mutations in the bone marrow of aAA patients using an unbiased genetic analysis, 2) Identify genomic biomarkers of response to therapy and disease outcomes, and 3) Characterize the function of candidate driver mutations in hematopoiesis. The successful completion of this project is expected to have a sustained and lasting impact in the field by providing an understanding of clinically-relevant somatic alterations in aAA, which could serve as genetic biomarkers and targets for new personalized therapies. The strong scientific expertise and the mentorship track-record of the PI's Mentor and Advisory Committee, together with the unique resources and outstanding research facilities at Penn make this an ideal environment for this K08 Award. This research program, performed in the context of a comprehensive career development plan, will support the PI's career transition to become an independent physician-scientist in Hematology.

Public Health Relevance

Acquired aplastic anemia is a rare, life-threatening blood disease, affecting children and adults, which is caused by immune destruction of early blood cells. Treatment failure and relapse are common; progression to blood cancers is a feared late complication, with no available prevention strategy. This proposal aims to understand genetic changes in aplastic anemia, in order to identify markers of disease response and progression, which can serve as targets for new personalized treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Clinical Investigator Award (CIA) (K08)
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NHLBI Mentored Clinical and Basic Science Review Committee (MCBS)
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Yang, Yu-Chung
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Babushok, Daria V (2018) A brief, but comprehensive, guide to clonal evolution in aplastic anemia. Hematology Am Soc Hematol Educ Program 2018:457-466
Soderquist, Craig R; Ewalt, Mark D; Czuchlewski, David R et al. (2018) Myeloproliferative neoplasms with concurrent BCR-ABL1 translocation and JAK2 V617F mutation: a multi-institutional study from the bone marrow pathology group. Mod Pathol 31:690-704
Babushok, Daria V; Nelson, Ernest J; Morrissette, Jennifer J D et al. (2018) Myelofibrosis patients can develop extramedullary complications including renal amyloidosis and sclerosing hematopoietic tumor while otherwise meeting traditional measures of ruxolitinib response. Leuk Lymphoma :1-4
Babushok, Daria V; Stanley, Natasha L; Morrissette, Jennifer J D et al. (2018) Germline duplication of ATG2B and GSKIP genes is not required for the familial myeloid malignancy syndrome associated with the duplication of chromosome 14q32. Leukemia 32:2720-2723
Sarthy, Jay; Zha, Ji; Babushok, Daria et al. (2018) Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype. Blood Adv 2:120-125
Babushok, Daria V; Duke, Jamie L; Xie, Hongbo M et al. (2017) Somatic HLA Mutations Expose the Role of Class I-Mediated Autoimmunity in Aplastic Anemia and its Clonal Complications. Blood Adv 1:1900-1910
Peslak, Scott A; Olson, Timothy; Babushok, Daria V (2017) Diagnosis and Treatment of Aplastic Anemia. Curr Treat Options Oncol 18:70
Stanley, Natasha; Olson, Timothy S; Babushok, Daria V (2017) Recent advances in understanding clonal haematopoiesis in aplastic anaemia. Br J Haematol 177:509-525
Reilly, Christopher R; Babushok, Daria V; Martin, Karlyn et al. (2017) Multicenter analysis of the use of transjugular intrahepatic portosystemic shunt for management of MPN-associated portal hypertension. Am J Hematol 92:909-914
Babushok, Daria V; Stanley, Natasha; Xie, Hongbo M et al. (2017) Clonal Replacement Underlies Spontaneous Remission in Paroxysmal Nocturnal Haemoglobinuria. Br J Haematol 176:487-490

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