Acute lymphoblastic leukemia (ALL) is a leading cause of cancer death in children. The goal of my research is to use integrated genomic and epigenomic profiling to define the genomic alterations that drive leukemogenesis and treatment failure in ALL, and to use this information to develop mouse models to translate these discoveries to innovative therapeutic approaches. My research program has revised the molecular taxonomy of ALL, identified constellations of genetic mutations that define subtypes of ALL, has dissected the genetic basis of clonal evolution, identified new targets for therapeutic intervention, notably with tyrosine kinase inhibitors, and has established several new engineered models of high-risk B-progenitor ALL. Recent advances include identification of a high frequency of mutations in epigenetic regulators at relapse in ALL, and demonstrating that specific genomic alterations perturb the interaction of leukemic cells with the microenvironment, resulting in resistance to therapy. This research proposal will determine the mechanistic basis by which genetic lesions present at diagnosis, or enriched at relapse, determine resistance to therapy, and exploit these for therapeutic intervention. Research goals are (1) to identify the constellations of genomic and epigenomic alterations that characterize each subtype of ALL across the age spectrum, and identifying those alterations that cause treatment failure. This involves genome and transcriptome sequencing of childhood and adult ALL, and integrated whole genome, whole genome bisulfite, transcriptome and chromatin mark sequencing of a cohort of 100 ALL cases, including matched samples obtained at diagnosis and relapse and corresponding xenografts. This is essential to identify all coding and non-coding mutations driving disease, to systematically examine the effect of genetic alterations on chromatin remodeling, and to guide the development and interpretation of mouse models of ALL. (2) To perform multiplexed loss-of-function screens using expression of founding oncogenic fusions, coupled with RNA interference and genome editing to dissect the interaction of polygenic alterations in leukemogenesis. (3) To use gene-specific and loss-of-function screens to examine the role of epigenomic alterations in ALL relapse. These include detailed characterization of Crebbp knockin models of ALL, and RNAi/CRISPR/Cas9 screens targeting over 700 chromatin modifier genes in B-ALL leukemia models. Enriched hits, and their effects on chromatin modeling and transcriptional regulation will be compared to data from human leukemic cells; and the resulting models used to test the effect of epigenetic modifying agents on modulating drug resistance. (4) To use mouse models of B-ALL to dissect the role of cellular mislocalization and ?hijacking? of the bone marrow niche and the role of this phenomenon in drug resistance. Together, these approaches provide a comprehensive strategy to fully define the genomic alterations driving treatment failure in ALL, and to mechanistically validate these in logical experimental systems to guide further drug development approaches.

Public Health Relevance

(RELEVANCE STATEMENT) Acute lymphoblastic leukemia (ALL) is the commonest childhood tumor and a leading cause of cancer death in children, adolescents and young adults. My research program has used genomic profiling and complementary experimental modeling to define the inherited and somatic genomic landscape of ALL, and to use this information to develop faithful models of leukemia to inform new diagnostic and treatment approaches. My research program will use innovative genomic, epigenomic and experimental approaches to develop this research in the following areas: comprehensive identification of genomic and epigenomic alterations associated with treatment failure in children and adult in ALL, establishing polygenic models of ALL to functionally validate genes driving leukemogenesis; modeling the role of epigenomic alterations at relapse in ALL, and studying the role of leukemic cell interactions with the bone marrow microenvironment as a mechanism of resistance. Together these approaches will provide fundamental genomic and mechanistic insights into the biology of ALL and provide new avenues for therapeutic intervention in this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA197695-01A1
Application #
9186853
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M2))
Program Officer
Mufson, R Allan
Project Start
2017-01-19
Project End
2023-12-31
Budget Start
2017-01-19
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$1,071,276
Indirect Cost
$471,276
Name
St. Jude Children's Research Hospital
Department
Type
Independent Hospitals
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Alexander, Thomas B; Gu, Zhaohui; Iacobucci, Ilaria et al. (2018) The genetic basis and cell of origin of mixed phenotype acute leukaemia. Nature 562:373-379
Slayton, William B; Schultz, Kirk R; Kairalla, John A et al. (2018) Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622. J Clin Oncol 36:2306-2314
Roberts, Kathryn G; Janke, Laura J; Zhao, Yaqi et al. (2018) ETV6-NTRK3 induces aggressive acute lymphoblastic leukemia highly sensitive to selective TRK inhibition. Blood 132:861-865
Churchman, Michelle L; Qian, Maoxiang; Te Kronnie, Geertruy et al. (2018) Germline Genetic IKZF1 Variation and Predisposition to Childhood Acute Lymphoblastic Leukemia. Cancer Cell 33:937-948.e8
Welsh, S J; Churchman, M L; Togni, M et al. (2018) Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis. Leukemia 32:38-48
Roberts, Kathryn G; Reshmi, Shalini C; Harvey, Richard C et al. (2018) Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group. Blood 132:815-824
Inaba, Hiroto; Azzato, Elizabeth M; Mullighan, Charles G (2017) Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia with Targetable Lesions: The St. Jude Children's Research Hospital Approach. Front Pediatr 5:258