The Role of SKIDA1 in Acute Myeloid Leukemia Initiation and Maintenance

SKIDA1 在急性髓系白血病发生和维持中的作用

基本信息

批准号：
10606263
负责人：
Jonny Mendoza-Castrejon
金额：
$ 3.36万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606263
关键词：
Acute Myelocytic Leukemia Adult Age Alleles Binding Biological Assay Blood Cells Cell Line Cells ChIP-seq Childhood Childhood Acute Myeloid Leukemia Childhood Leukemia Chimeric Proteins Chromatin Chromosomal translocation Co-Immunoprecipitations Collecting Cell Data Dependence Development Doxycycline Embryo Enhancers Frequencies Gene Expression Genes Genetic Enhancer Element Genetic Transcription Genetic study Genome Goals Hematopoiesis Hematopoietic System Hematopoietic stem cells Human Infant Infant Leukemia Knockout Mice Life Link LoxP-flanked allele MLL gene MLL-AF9 Maintenance Maps Mixed-Lineage Leukemia Monitor Mus Mutation Neonatal Neonatal Leukemia Pattern Preleukemia Retroviridae Role Testing Transplantation Work acute myeloid leukemia cell adult leukemia age related cellular transduction conditional knockout driver mutation experimental study innovation leukemia leukemogenesis loss of function mouse genetics mouse model neonate novel novel therapeutics postnatal progenitor programs promoter response self-renewal single-cell RNA sequencing targeted treatment transcriptome transcriptome sequencing

项目摘要

ABSTRACT Chromosomal translocations involving the MLL1 gene often drive infant acute myeloid leukemia (AML). MLL fusion proteins (e.g., MLL-ENL, MLL-AF9, MLL-AF10) activate self-renewal programs in hematopoietic stem and progenitor cells, ultimately leading to transformation. The high frequency of MLL1 rearrangements in infant leukemias suggests that neonatal progenitors are uniquely poised to transform in response to these mutations. Indeed, we have recently shown that MLL-ENL initiates AML more efficiently in neonatal progenitors than in adult progenitors. This raises the question of whether MLL-ENL induces key effectors of transformation more efficiently in neonatal progenitors than in adult progenitors. We identified Ski/Dach Domain Containing 1 (Skida1) as a gene that is highly induced by MLL-ENL in neonatal, but not adult hematopoietic progenitors. SKIDA1 is also highly expressed in human pediatric MLL1 rearranged AML. Expression is largely restricted to leukemias with MLL1 rearrangements. To test whether Skida1 promotes leukemogenesis, we generated a germline loss-of-function mouse allele. Skida1 deletion by itself had negligible effects on normal hematopoiesis, consistent with the lack of expression in normal hematopoietic progenitors. Furthermore, Skida1 deletion did not affect normal HSC function. However, when we induced MLL-ENL expression in Skida1-/- neonates, we observed near complete loss of HSCs and a severe reduction in lineage committed hematopoietic progenitor cells (HPCs). Thus, Skida1-dependence emerges as a consequence of MLL-ENL expression. Next, we generated a conditional loss-of-function mouse allele. Skida1 conditional deletion in the hematopoietic system did not perturb normal hematopoiesis at any age. We are currently crossing the conditional Skida1 mouse to our MLL-ENL mouse model to test whether Skida1 promotes leukemogenesis in the context of MLL-ENL-expressing progenitors. Thus, I hypothesize that Skida1 sustains pre-leukemic HSCs and HPCs and promotes AML during neonatal stages of life. Aim 1 will use a Skida1 conditional knockout mouse to interrogate how Skida1 sustains MLL-ENL-expressing HSCs and HPCs. I will also test whether Skida1 is necessary to maintain fully transformed AML cells. Aim 2 builds upon Aim 1 by adding mechanistic studies to identify Skida1-dependent changes in gene expression and cell fate. I will test whether SKIDA1 binds chromatin to regulate leukemogenesis, and I will identify SKIDA1 binding partners. The aims of this proposal will evaluate SKIDA1 as a potential link between age-specific transcriptional programs and AML initiation, as well as offer a novel therapeutic vulnerability for treating infant leukemia.

抽象的涉及MLL1基因的染色体易位通常会驱动婴儿急性髓样白血病（AML）。 MLL 融合蛋白（例如MLL-ENL，MLL-AF9，MLL-AF10）激活造血茎中的自我更新程序和祖细胞，最终导致转化。婴儿中MLL1重排的高频白血病表明，新生儿祖细胞被唯一地准备在这些突变中转变。确实，我们最近表明，MLL-ENL比在新生儿祖细胞中更有效地启动AML 成人祖先。这就提出了一个问题，即MLL-ENL是否诱导转化的关键效应因素更多与成人祖细胞相比，在新生儿祖细胞中有效。我们确定了包含1的滑雪/dach域（skida1）作为一种基因，在新生儿，但不是成年造血祖细胞中高度诱导的基因。 Skida1在人的小儿MLL1重排AML中也高度表达。表达在很大程度上仅限于白血病与MLL1重排。为了测试Skida1是否促进白血病，我们产生了一个种系功能丧失的鼠标等位基因。 skida1删除本身对正常有可忽略的影响造血，与正常造血祖细胞中缺乏表达一致。此外， SKIDA1缺失不会影响正常的HSC功能。但是，当我们诱导MLL-ENL表达时 Skida1 - / - 新生儿，我们观察到HSC几乎完全丢失，并严重降低了所做的谱系造血祖细胞（HPC）。因此，skida1依赖性由于mll-enl而出现表达。接下来，我们产生了有条件的功能丧失鼠标等位基因。 Skida1有条件删除造血系统在任何年龄均不会扰动正常造血。我们目前正在越过有条件的Skida1小鼠到我们的MLL-ENL小鼠模型，以测试SKIDA1是否促进了白血病。表达MLL-Enl的祖细胞的上下文。因此，我假设skida1维持了美食前HSC 在新生儿阶段，HPC并促进AML。 AIM 1将使用SKIDA1条件淘汰赛鼠标询问Skida1如何维持表达MLL-Enl的HSC和HPC。我还将测试是否 Skida1对于维持完全转化的AML细胞是必要的。 AIM 2通过添加机械来建立AIM 1 鉴定基因表达和细胞命运的Skida1依赖性变化的研究。我将测试Skida1是否结合染色质以调节白血病，我将识别skida1结合伴侣。这个目的提案将评估SKIDA1作为特定年龄转录程序与AML之间的潜在联系启动，并为治疗婴儿白血病提供了一种新颖的治疗脆弱性。