Relapsed leukemia is chemotherapy resistant, survival is poor, and the molecular mechanisms underlying resistance remain poorly understood. Recurrent mutations in the chromatin modifier SETD2 were recently described to be enriched in relapsed pediatric acute lymphoblastic leukemia patients (Mar et al, 2014). Preliminary data suggests that SETD2 loss leads to chemotherapy resistance through impaired DNA damage response (DDR) and a resultant failure to trigger apoptosis to DNA damaging agents. The goal of the proposed research project is to characterize the chemotherapy resistance associated with SETD2 loss and define its mechanism of action. To better understand the resistance induced by SETD2 loss and its relevance to leukemia, this proposal utilizes several newly developed in vitro and in vivo models of SETD2 loss, including a novel conditional murine knockout of Setd2 and engineered isogenic leukemia cell lines with SETD2 loss. Leukemia chemotherapy agents with different mechanisms of inducing cell death, including various types of DNA damage, will be used in these models of SETD2 loss to gain insight into the potential defects in DNA damage signaling. Findings in vitro will be studied in vivo to understand how a more physiological leukemia engraftment and chemotherapy exposure alters therapy resistance. The mechanism of resistance will be elucidated by closely examining the components of the DDR, the requirement for SETD2 catalytic function and how SETD2 loss affects the local chromatin distribution of DDR mechanisms and DNA damage. In summary, SETD2 loss is a novel mechanism of chemotherapy resistance in leukemia, and this proposal seeks to substantially advance our understanding of this clinically relevant lesion. Candidate: Dr. Brenton Mar is an instructor in Pediatric Hematology/Oncology at Boston Children's Hospital who aims to become an independent tenure track physician-scientist working on roles of epigenetic regulators in leukemogenesis and chemotherapy resistance. He has outlined a 5 year period of mentored training to strengthen his skills in disease modeling and functional genomics. This training period will be carried out under the mentorship of Dr. Benjamin Ebert, a recognized leader in leukemia biology and hematopoiesis. He has also assembled an advisory committee composed of Dr. Alan D'Andrea, Dr. James Griffin, Dr. Lewis Silverman and Dr. Charlie Roberts that will help guide him in his training and research. Environment: The Dana-Farber Cancer Institute and Boston Children's Hospital in the Harvard Medical area have an internationally recognized research program in Pediatric Hematology/Oncology with areas of expertise in hematopoiesis, epigenetics, transcription, DNA damage response, tumor biology, and the genetics of hematologic and malignant diseases. Intellectual interactions and collaboration are fostered by weekly research seminars. The division has a long track record of mentorship and producing the nation's leaders in hematology and oncology research.

Public Health Relevance

As leukemia relapses, it acquires increasing resistance to chemotherapy, but the mechanisms underlying this process are not well understood. I have found that patients with relapsed pediatric acute lymphoblastic leukemia (ALL) acquire mutations in the SETD2 gene, and my preliminary data suggests that this leads to resistance to a number of commonly used chemotherapy agents. My research proposal seeks to substantially advance our understanding of this clinically relevant lesion by defining how it leads to resistance and how it can be eventually reversed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA184419-01A1
Application #
9109772
Study Section
Subcommittee J - Career Development (NCI-J)
Program Officer
Lim, Susan E
Project Start
2016-07-01
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$177,120
Indirect Cost
$13,120
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Li, Hubo; Mar, Brenton G; Zhang, Huadi et al. (2017) The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 129:497-508
Mar, Brenton G; Chu, S Haihua; Kahn, Josephine D et al. (2017) SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia. Blood 130:2631-2641