The applicant proposes a five year plan to provide the candidate with mentored research and career development training. He recently completed his formal training in the Hematology/Oncology fellowship (and Physician Scientist Training Program) at Washington University School of Medicine and was promoted to an Instructor of Medicine in the Division of Oncology. At this juncture of his career, he desires additional mentored support to facilitate his scientific and career goals. The ultimate goal of the candidate is to be an independent investigator in an academic medical center, studying normal and malignant hematopoiesis and taking care of patients with hematologic diseases and cancer. The experiments outlined in this application aim to understand the role of chemotherapy in promoting the competitive fitness advantage and subsequent expansion of certain chemo-resistant hematopoietic clones and its potential clinical ramifications. The proposed studies will be carried out at Washington University under the primary mentorship of Dr. Daniel Link. Dr. Link is a world- renowned leader in the field of hematopoiesis. He is also a highly experienced and well-regarded mentor who has successfully mentored numerous trainees to independence. Therapy-related acute myeloid leukemia (t-AML) and therapy-related myelodysplastic syndrome (t-MDS) are well-recognized complications of cytotoxic chemotherapy and/or radiotherapy (Godley, et al; Semin Oncol 2008). The long-term goal of our research is to determine how exposure to cytotoxic therapy contributes to leukemogenesis. Hematopoietic stem and progenitor cells (HSPCs) accumulate somatic mutations during the normal aging process, resulting in a genetically heterogeneous HSPC population in healthy adult individuals (Welch, et al; Cell 2012). In our preliminary data, we used a sensitive error-corrected next-generation sequencing (NGS) approach to identify functional TP53 mutations in very small populations of peripheral blood leukocytes in healthy elderly individuals. Furthermore, in several cases of t-AML/t-MDS, we found that the driver TP53 mutation clonal at diagnosis was in fact present at low frequencies in the bone marrow prior to the initiation of chemotherapy. Based on these data, we hypothesize that cytotoxic therapy is providing a selective pressure resulting in a fitness advantage to HSPCs harboring certain somatic mutations, including those in TP53. To further expand upon this hypothesis, the following specific aims are proposed: 1) Determine the incidence and assess the clonal expansion of HSPCs harboring TP53 mutations in patients with relapsed/refractory lymphoma undergoing autologous stem cell transplantation, 2) Identify additional somatic mutations providing HSPCs with a competitive fitness advantage after cytotoxic chemotherapy and autologous transplantation, and 3) Characterize the mechanisms by which TP53 mutations confer competitive fitness to HSPCs after chemotherapy. These proposed experiments will define the degree to which intensive chemotherapy influences the clonal evolution of hematopoietic stem cells and define the mechanisms through which somatic mutations in TP53 (and related genes) provide certain HSPCs with a fitness advantage. Ultimately, we hope to develop diagnostic tools for the risk stratification and early detection of -AML/t-MDS and potentially prevent the evolution of this poor prognosis disease. In particular, a better understanding of the mechanisms by which functional TP53 mutations result in clonal HSPC expansion after chemotherapy may lead to strategies to potentially reduce the risk of t-AML/t-MDS.
Therapy-related AML (t-AML) and therapy-related MDS (t-MDS) are poor prognosis complications of cytotoxic chemotherapy and/or radiotherapy. The proposed studies will (1) define the degree to which certain hematopoietic stem and progenitor cells (HSPCs) (e.g. those with somatic mutations in TP53) gain a competitive fitness advantage under the selection pressure of chemotherapy and (2) explore the mechanisms behind this fitness advantage. A better understanding of the mechanisms through which functional TP53 mutations result in clonal HSPC expansion after cytotoxic therapy exposure may eventually lead to strategies to reduce the risk of t-AML/t-MDS.
|Wong, Terrence N; Miller, Christopher A; Jotte, Matthew R M et al. (2018) Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat Commun 9:455|
|Trissal, Maria C; Wong, Terrence N; Yao, Juo-Chin et al. (2018) MIR142 Loss-of-Function Mutations Derepress ASH1L to Increase HOXA Gene Expression and Promote Leukemogenesis. Cancer Res 78:3510-3521|