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Transcriptional Determinants of L-Asparaginase Response in Leukemia

白血病 L-天冬酰胺酶反应的转录决定因素

基本信息

批准号：
10316164
负责人：
Robert Thomas Williams
金额：
$ 3.52万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-13 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10316164
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Affect Amino Acids Asparagine Aspartate-Ammonia Ligase BTB/POZ Domain Binding Biological Assay CRISPR/Cas technology Cancer cell line Cell Line Cells ChIP-seq Childhood Chromatin DNA Binding DNA-Directed RNA Polymerase Drug Targeting Electrophoretic Mobility Shift Assay Enzymes Exhibits Face Fellowship Genes Genetic Screening Genetic Transcription Genome Guide RNA Hematology Human Immunocompromised Host Immunoprecipitation Impairment In Vitro Individual Investigation Knock-out Laboratories Leukemia Acute Lymphoblastic Chemotherapy Leukemic Cell Libraries Luciferases MLL gene Malignant Childhood Neoplasm Malignant neoplasm of lung Mass Spectrum Analysis Massive Parallel Sequencing Mediating Mus Oncology Patients Physicians Play Prognostic Marker Proteins RNA Polymerase II Recombinants Regulation Relapse Reporter Residencies Resistance Resistance development Risk Role Scientist Serum Subgroup Survival Rate T-Lymphocyte Testing Training Transcription Elongation Transcription Initiation Transcriptional Regulation Transposase Universities Up-Regulation Work Zinc Fingers activating transcription factor 4 acute lymphoblastic leukemia cell asparaginase career cell growth chromatin immunoprecipitation clinically relevant deprivation design experimental study genome-wide high risk histone modification in vivo insight leukemia malignant breast neoplasm pancreatic cancer cells programs promoter recruit resistance mechanism response therapeutic target transcription factor

项目摘要

Project Summary/Abstract L-asparaginase is a bacterial enzyme that depletes serum asparagine to inhibit leukemic cell growth in acute lymphoblastic leukemia. Some patients do not respond to L-asparaginase and the cellular mechanisms underlying non-response remain poorly understood. Under asparagine deprivation, cells activate a transcriptional program known as the amino acid deprivation response that is mediated by activating transcription factor 4 (ATF4). This program culminates in the expression of asparagine synthetase (ASNS), the enzyme responsible for the synthesis of asparagine. Other than ATF4, the transcriptional regulators involved in this response are poorly defined. To identify transcriptional genes involved in the response to L-asparaginase, I developed a CRISPR-Cas9 genetic screening approach to individually knock out each transcription-related gene in the genome. This approach allowed determination of genes that were required for the resistance of an ALL cell line to L- asparaginase. The top-scoring gene in my preliminary genetic screen was a poorly described transcription factor, ZBTB1. Knockout of ZBTB1 sensitized this ALL cell line to treatment with L-asparaginase. Preliminary work suggested that ZBTB1 enriches in the promoter of ASNS to promote transcription. I hypothesize that ZBTB1 and the regulation of ASNS expression may be a suitable drug target in asparaginase resistant leukemia. A lack of insight into the mechanistic role of ZBTB1 in mediating transcription, however, precludes investigation of this hypothesis. In this proposal, building on my preliminary work, I will test the hypothesis that ZBTB1 positively regulates the transcription of ASNS and may be a therapeutic target for L-asparaginase resistant ALLs. In Aim 1, I will investigate the mechanism by which ZBTB1 regulates the expression of ASNS. In Aim 2, I will determine whether ZBTB1 knockout sensitizes human ALL cell lines and primary human ALLs to treatment with L- asparaginase in vivo. I anticipate that these studies will determine: 1) the mechanistic role of ZBTB1 in the response to L-asparaginase in leukemic cells and 2) the potential of ZBTB1 as a therapeutic target in L- asparaginase resistant ALL. This work will be completed in the laboratory of Dr. Kivanc Birsoy with the co- advisement of Dr. Robert Roeder at the Rockefeller University. The training plan outlined in this proposal is designed to best prepare me for a career as an independent physician-scientist following residency and fellowship training in hematology and oncology.

项目总结/文摘

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dietary thiamine influences l-asparaginase sensitivity in a subset of leukemia cells.

DOI：
10.1126/sciadv.abc7120
发表时间：
2020-10
期刊：
Science advances
影响因子：
13.6
作者：
Guarecuco R;Williams RT;Baudrier L;La K;Passarelli MC;Ekizoglu N;Mestanoglu M;Alwaseem H;Rostandy B;Fidelin J;Garcia-Bermudez J;Molina H;Birsoy K
通讯作者：
Birsoy K