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Investigating the role of KAT6A in MLL-rearranged acute myeloid leukemia

研究 KAT6A 在 MLL 重排急性髓系白血病中的作用

基本信息

批准号：
10686801
负责人：
Mario Andres Blanco
金额：
$ 36.55万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686801
关键词：
Ablation Acute Myelocytic Leukemia Binding Biochemical Biological Assay CRISPR screen Cell Cycle Cell Differentiation process Cell Proliferation Cell Survival Cells ChIP-seq Chimeric Proteins Chromatin Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex DNMT3a Data Differentiation Therapy Disease Disease Progression Disease remission ENL Protein Epigenetic Process FLT3 gene Gene Expression Genes Genetic Genetic Transcription Goals Hematologic Neoplasms Hematopoiesis Human Impairment In Vitro Individual KDM1A gene Knock-out MLL-AF9 MLL-rearranged leukemia Mass Spectrum Analysis Methodology Methods Methylcellulose Modeling Molecular Mus Myelogenous Oncogenes Patients Pharmaceutical Preparations Play Progranulocytes Proliferating Reader Role Sampling Scheme Tertiary Protein Structure Testing Therapeutic Toxic effect Work Xenograft Model acute myeloid leukemia cell burden of illness chemotherapy combinatorial design epigenome epigenomics histone acetyltransferase histone-binding proteins in vivo inhibitor mouse model mutant novel programs promoter protein complex recruit response self-renewal small molecule stemness success synergism targeted treatment therapeutic evaluation therapeutic target transcription factor transcriptome transcriptome sequencing transplant model treatment effect

项目摘要

Acute myeloid leukemia (AML) is a disease of blocked differentiation in which blasts fail to mature and proliferate continuously. Differentiation therapy, which aims to reactivate latent maturation programs and induce cell cycle exit, is curative in the promyelocytic (APL) AML subtype, but not in other AML subtypes. Epigenetic factors help sustain the differentiation block, and inhibitors of regulators such as the LSD1, BRD4, and DOT1L has recently been shown to re-activate myeloid differentiation programs in selected AML models. However, these inhibitors generally do not achieve terminal differentiation and disease remission. Accordingly, there is significant need to identify more regulators of the AML differentiation block and to test whether their inhibitors can induce terminal differentiation when used individually or in combination regiments. To identify novel regulators of AML differentiation, we recently performed a chromatin-focused CRISPR sgRNA screen using gain-of- differentiation as a readout. This screen identified the H3K9 histone acetyltransferase KAT6A as a key driver of AML differentiation arrest, and mechanistic work showed that KAT6A and the H3K9ac histone binding protein ENL closely cooperate to active promoters of AML oncogenes. We confirmed that both genetic (CRISPR) and small molecule inhibition of KAT6A markedly induces differentiation and reduces proliferation most commonly in MLL-rearranged (MLL-r) AMLs, and also in selected MLL-wild type (MLL-WT) AMLs. Further, KAT6A inhibitors synergize with inhibitors of either LSD1 or DOT1L to induce near-terminal differentiation and fully halt proliferation in vitro. This proposal has three goals: First, we will determine the mechanisms by which KAT6A and ENL are recruited to chromatin and activate transcription. We will identify the protein domains in KAT6A and the MOZ complex it resides in that are responsible for its binding to chromatin at MLL-AF9 targets and non- MLL-AF9 targets. We will also identify any transcription factors interacting with KAT6A and ENL and test their effect on recruitment of the KAT6A-ENL module to chromatin. Our second goal is to test the therapeutic potential of targeting KAT6A, individually or in combination with LSD1 or DOT1L inhibitors, in genetically-defined AML mouse models. We will employ an Mll-Af9 model and a Dnm3a/Flt3-ITD model and test the effect of inhibitor treatment schemes on disease progression and overall survival. We will also test the effect of inhibitor treatments on normal hematopoiesis. Our third goal will be to test the response of clinical AML patient samples to inhibition of KAT6A, individually or in combination with LSD1 or DOT1L inhibitors. We will perform drug response assays in MLL-r and MLL-WT samples in vitro using OP9 feeder layer culturing methodology, and will also perform PDX transplant models and test the response to KAT6A and LSD1 or DOT1L inhibitors in vivo.

急性髓性白血病（AML）是一种细胞分化受阻的疾病