Over 50,000 people will be diagnosed with a myeloid neoplasm this year in the U.S. alone. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common adverse-risk prognostic indicator in de novo acute myeloid leukemia. Leukemias with -7/del(7q) are resistant to treatment, and this subset of patients has a median over- all survival o less then a year. -7/del(7q) also occurs in half of therapy-related myeloid neoplasms, which arise as a devastating side-effect of chemotherapy and radiation in survivors of a prior cancer. The long-term goal of this proposal is to understand the molecular abnormalities of -7/del(7q) to develop new treatment strategies for these patients. I recently discovered that a transcription factor gene, CUX1, is within the commonly deleted segment of chromosome band 7q. I found that CUX1 is a highly conserved, haploinsufficient myeloid tumor suppressor gene using in vivo models. I identified a CUX1-associated cell cycle gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. The objective of this proposal is to identify the genes and pathways regulated by CUX1 and how CUX1 haploinsufficiency alters these path- ways in leukemia. Based on preliminary data, I hypothesize that CUX1 suppresses tumor growth by blocking proliferation and promoting differentiation. This hypothesis will be tested by innovative genomic analyses and complementary in vivo studies.
In Aim 1, I will identify the CUX1 transcriptional targets in human hematopoietic stem cells and the aberrant CUX1 targets in primary acute myeloid leukemia samples. I will use this data to determine the cis-regulatory logic that defines those gene targets that are sensitive to haploinsufficient CUX1 levels.
In Aim 2, I will identify the mechanism of CUX1 tumor suppressor activity, using a tractable, in vivo, model with human hematopoietic stem cells xenografted in immunodeficient mice. These experiments will establish the role for CUX1 in myeloid lineage specification, growth, and self-renewal. These studies will reveal those genes and pathways that are induced by CUX1 haploinsufficiency. These results are critical for future R01-level studies to identify drugs that inhibit downstream effectors of CUX1. I propose a five-year career development plan so as to establish myself as a leader in myeloid cancer genomics. My training is comprised of didactics, institutional resources, and supervised research in computational biology, biostatistics, and myeloid biology. I have assembled a first-class team of mentors and advisors to oversee this training: Kevin White, a leader in the field of genomics and systems biology, and internationally recognized experts in the fields of bioinformatics, biostatistics, myeloid neoplasi biology. With this training in the rich academic environment of the University of Chicago, a long-term world leader in the study of in myeloid neoplasia and genomics, I will develop into a translational physician-scientist who can bridge the gulf between medicine and next-generation genomics in the study of hematopoietic malignancies.
Over 50,000 people are diagnosed with myeloid neoplasms in the United States each year, and a subset of patients carry a high-risk cytogenetic abnormality, -7/del(7q), which indicates treatment resistance and carries a poor prognosis. -7/del(7q) occurs in half of therapy-related myeloid neoplasms, which are a devastating side-effect of chemotherapy and radiation in patients that survived a prior cancer. This proposal will use complementary in vivo models and innovative genomic approaches to identify the molecular abnormalities that drive -7/del(7q) myeloid neoplasms. This research will ultimately lead to the identification of new therapeutic targets to improve the outcome for patients with this disease.
|An, Ningfei; Khan, Saira; Imgruet, Molly K et al. (2018) Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS. Blood 131:2682-2697|
|McNerney, Megan E; Godley, Lucy A; Le Beau, Michelle M (2017) Therapy-related myeloid neoplasms: when genetics and environment collide. Nat Rev Cancer 17:513-527|
|Arthur, Robert K; An, Ningfei; Khan, Saira et al. (2017) The haploinsufficient tumor suppressor, CUX1, acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters. Nucleic Acids Res 45:6350-6361|
|Stoddart, Angela; Qian, Zhijian; Fernald, Anthony A et al. (2016) Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasms. Haematologica 101:e232-6|
|Voce, D J; Schmitt, A M; Uppal, A et al. (2015) Nfkb1 is a haploinsufficient DNA damage-specific tumor suppressor. Oncogene 34:2807-13|
|Zhao, Zhen; Chen, Chi-Chao; Rillahan, Cory D et al. (2015) Cooperative loss of RAS feedback regulation drives myeloid leukemogenesis. Nat Genet 47:539-43|
|McNerney, Megan E; Brown, Christopher D; Peterson, April L et al. (2014) The spectrum of somatic mutations in high-risk acute myeloid leukaemia with -7/del(7q). Br J Haematol 166:550-6|
|Heath, Allison P; Greenway, Matthew; Powell, Raymond et al. (2014) Bionimbus: a cloud for managing, analyzing and sharing large genomics datasets. J Am Med Inform Assoc 21:969-75|