更新于：2024-05-01

ASXL1

ASXL transcriptional regulator 1

更新于：2024-05-01

基本信息

别名

Additional sex combs-like protein 1、ASXL transcriptional regulator 1、ASXL1

+ [2]

简介

Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG) (PubMed:16606617). Acts as coactivator of RARA and RXRA through association with NCOA1 (PubMed:16606617). Acts as corepressor for PPARG and suppresses its adipocyte differentiation-inducing activity (By similarity). Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1) (PubMed:20436459). Acts as a sensor of N(6)-methyladenosine methylation on DNA (m6A): recognizes and binds m6A DNA, leading to its ubiquitination and degradation by TRIP12, thereby inactivating the PR-DUB complex and regulating Polycomb silencing (PubMed:30982744).

关联

项与 ASXL1 相关的药物

CER-1236

靶点-

作用机制

ASXL1 调节剂 [+2]

在研机构

CERo Therapeutics Holdings, Inc. [+1]

原研机构

CERo Therapeutics, Inc.初创企业

在研适应症

急性髓性白血病 [+2]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ASXL1 相关的临床结果

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100 项与 ASXL1 相关的转化医学

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0 项与 ASXL1 相关的专利（医药）

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1,357

项与 ASXL1 相关的文献（医药）

2024-03-01·Hematological oncology

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt-related transcription factor 1 mutation: A single-center retrospective analysis.

Article

作者: Lin-Ya Wang ; Yao Li ; Qian Jiang ; Hao Jiang ; Yu Wang ; Lan-Ping Xu ; Xiao-Hui Zhang ; Kai-Yan Liu ; Fei-Fei Tang

This study aimed to investigate the clinical characteristics and prognosis of Runt-related transcription factor 1 (RUNX1) mutant acute myeloid leukemia (AML) patients by comparing the features of AML patients with or without RUNX1 mutation. We retrospectively analyzed 180 AML patients including 36 AML patients with mutant RUNX1(AML-RUNX1^mut ) and 144 AML patients with wild-type RUNX1(AML-RUNX1^wt ) were selected using the case-pair method(1:4). Compared to AML-RUNX1^wt , AML-RUNX1^mut showed higher frequency of ASXL1 (p < 0.001), SRSF2 (p < 0.001), BCORL1 (p < 0.001), RAS (p = 0.010) mutations, and absent NPM1 mutations (p = 0.022). The 3-year overall survival (OS) and disease-free survival (DFS) of AML-RUNX1^mut and AML-RUNX1^wt were 73.1% versus 68.0% (p = 0.64) and 80.7% versus 71.6% (p = 0.37), respectively. AML-RUNX1^mut receiving allogeneic hematopoietic cell transplantation (allo-HSCT) showed better survival than those who did not receive allo-HSCT (3-year OS, 84.3% vs. 52.7%; p = 0.006). Multivariate analysis showed that EZH2 mutation (p = 0.003), white blood cell (WBC) ≥30 × 10⁹ /L (p = 0.036) and age ≥60 years (p = 0.038) were significant independent risk factors for inferior OS of AML-RUNX1^mut ; WBC ≥30 × 10⁹ /L (p = 0.013) and DNMT3A mutation (p = 0.045) were significant independent risk factors for shorter DFS of AML-RUNX1^mut . In conclusion, AML-RUNX1^mut showed unique clinical characteristics, but the survival between AML-RUNX1^mut and AML-RUNX1^wt were comparable. EZH2 co-mutation, DNMT3A co-mutation, old age and high WBC count were associated with inferior survival of AML-RUNX1^mut . Allo-HSCT can significantly improve the prognosis of AML-RUNX1^mut .

2024-02-22·Haematologica

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Article

作者: Déborah Meyran ; Chloé Arfeuille ; Sylvie Chevret ; Quentin Neven ; Aurélie Caye-Eude ; Elodie Lainey ; Arnaud Petit ; Fanny Rialland ; Gérard Michel ; Dominique Plantaz ; Charlotte Jubert ; Alexandre Theron ; Virginie Gandemer ; Marie Ouachée-Chardin ; Catherine Paillard ; Bénédicte Bruno ; Nimrod Buchbinder ; Cécile Pochon ; Charlotte Calvo ; Mony Fahd ; André Baruchel ; Hélène Cavé ; Jean-Hugues Dalle ; Marion Strullu

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.

2024-02-22·Clinical cancer research : an official journal of the American Association for Cancer Research

Broad next generation integrated sequencing of myelofibrosis identifies disease-specific and age-related genomic alterations.

Article

作者: Malathi Kandarpa ; Dan Robinson ; Yi-Mi Wu ; Tingting Qin ; Kristen Pettit ; Qing Li ; Gary Luker ; Maureen Sartor ; Arul Chinnaiyan ; Moshe Talpaz

PURPOSE:

Myeloproliferative neoplasms (MPNs) are characterized by the overproduction of differentiated myeloid cells. Mutations in JAK2, CALR and MPL are considered drivers of Bcr-Abl-ve MPNs, including essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic primary myelofibrosis (prePMF) and overt myelofibrosis (MF). However, how these driver mutations lead to phenotypically distinct and/or overlapping diseases is unclear.

EXPERIMENTAL DESIGN:

To compare the genetic landscape of MF to ET/PV/PrePMF, we sequenced 1711 genes for mutations along with whole transcriptome RNA-seq of 137 MPN patients.

RESULTS:

In addition to driver mutations, 234 and 74 genes were found to be mutated in overt MF (N=106) and ET/PV/PrePMF (N=31), respectively. Overt MF had more mutations compared to ET/PV/prePMF (5 vs 4 per subject, P=0.006). Genes frequently mutated in MF included high-risk genes (ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1), and Ras pathway genes. Mutations in NRAS, KRAS, SRSF2, EZH2, IDH2 and NF1, were exclusive to MF. Advancing age, higher DIPSS and poor overall survival (OS) correlated with increased variants in MF. Ras mutations were associated with higher leukocytes and platelets, and poor OS. The comparison of gene expression showed upregulation of proliferation and inflammatory pathways in MF. Notably, ADGRL4, DNASE1L3, PLEKHGB4, HSPG2, MAMDC2 and DPYSL3 were differentially expressed in hematopoietic stem and differentiated cells.

CONCLUSIONS:

Our results illustrate that evolution of MF from ET/PV/PrePMF likely advances with age, accumulation of mutations, and activation of proliferative pathways. The genes and pathways identified by integrated genomics approach provide insight into disease transformation and progression, and potential targets for therapeutic intervention.

项与 ASXL1 相关的新闻（医药）

2024-03-12

·今日头条

PNAS二连发！陈赛娟院士/任瑞宝研究员/沈杨主任医师团队等联合发文

本文为转化医学网原创，转载请注明出处作者：Sophia 导读： 2024年2月，上海血液学研究所沈杨和陈赛娟团队、上海血液学研究所任瑞宝团队、海南医学院衰老与肿瘤国际研究中心、海南医学院基础医学与生命科学学院蔡望伟团队、浙江大学附属第一医院金洁团队、苏州大学附属第一医院吴德沛团队合作，在 PNAS 背靠背发表文章，分别揭示了衰老相关的克隆造血（Clonal Hematopoiesis，CH）作为疾病风险评估生物标志的潜在应用价值和 AML 分子发病原理的核心特征及临床预后意义。研究一 01 克隆造血（CH）代表由体细胞突变驱动的造血干细胞及其后代的克隆扩增。CH的准确风险评估对于疾病预防和临床决策至关重要。CH 的大小已被证明与较高的疾病风险相关，但影响 CH 大小的因素尚不清楚。此外，CH在长寿个体中的特征没有得到很好的记录。 2024年2月15日，任瑞宝、蔡望伟教授联合团队（王凯、张文、易雳为论文共同第一作者）在PNAS发表题为“The impact of age and number of mutations on the size of clonal hematopoiesis”的研究论文，研究发现， CH的患病率在长寿老年组中明显更高，这表明CH在某些条件下可能有利于延长寿命。 https://www-pnas-org.libproxy1.nus.edu.sg/doi/10.1073/pnas.2319364121 在这里，我们报告了长（≥90岁）和普通（60~89岁）老年群体中CH的深入分析。利用靶向深度测序，我们发现 CH的发展与年龄和衰老生物标志物的表达密切相关。长龄组 CH 的发生率显著升高，TET2 和 ASXL1 突变的频率显著升高，提示某些 CH 可能有利于延长寿命。有趣的是，在60至110岁之间，CH的大小既不与年龄显著相关，也与衰老生物标志物的表达无关。相反，我们发现大CH大小与每个个体的突变数量之间存在很强的相关性。这些发现为CH提供了风险评估生物标志物，也表明CH的演变除了年龄外还受到因素的影响。研究二 02 急性髓系白血病（AML）是一种与衰老相关的异质性造血恶性肿瘤。尽管克隆性造血（CH）成为衰老和癌症研究的模型，但在急性髓系白血病（AML）中，衰老过程中的基因组和转录组学改变尚未完全阐明。 2024年2月29日，沈杨、陈赛娟、吴德沛、金洁教授联合团队（李剑峰、程雯艳、林祥杰、文丽君、王凯、朱勇梅为论文共同第一作者）在PNAS发表了题为“Aging and comprehensive molecular profiling in acute myeloid leukemia”的研究论文，研究提供了关于衰老如何塑造AML发病机制的见解，并有助于确定风险因素和分子靶点。 https://www-pnas-org.libproxy1.nus.edu.sg/doi/10.1073/pnas.2319366121 本研究共纳入1474例具有RNA测序数据的新诊断AML患者，94%的病例获得靶向或全外显子组测序数据。系统分析了衰老相关因素的相关性，包括年龄和克隆造血（CH）、性别和基因组/转录组学谱（基因融合、基因突变和基因表达网络或通路）。总体而言， 60岁及以上的AML患者预后明显不佳。随着年龄的增长，世界卫生组织分类中定义的基因融合频率降低，而基因突变的阳性率，尤其是与CH相关的基因突变，则增加。此外，基因融合阴性（GF-）患者的基因突变数量高于 GF 患者。根据 CH 和骨髓增生异常综合征（MDS）相关突变的状态，在 GF-AML 队列中确定了 3 个突变亚组，即 CH-AML、CH-MDS-AML 和其他 GF-AML。值得注意的是，CH-MDS-AML 在老年和男性病例、血细胞减少和显著不良临床结局中占主导地位。此外，包括HOXA/B、血小板因子和炎症反应在内的基因表达网络是与AML衰老和不良预后相关的最显著特征。因此，我们的工作揭示了不同年龄、性别和分子群体之间AML相互作用的复杂调节回路。参考资料： https://www-pnas-org.libproxy1.nus.edu.sg/doi/10.1073/pnas.2319364121 https://www-pnas-org.libproxy1.nus.edu.sg/doi/10.1073/pnas.2319366121 https://hainmc.edu.cn/news/info/1008/29601.htm 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！点击对应文字查看详情

临床研究

2024-03-11

·生物探索

PNAS | 海南医学院任瑞宝/蔡望伟/上海交通大学陈竺揭示年龄和突变数对克隆造血大小的影响

引言克隆性造血( CH )是指造血干细胞及其子代在体细胞突变驱动下的克隆性增殖。准确的CH风险评估对疾病预防和临床决策至关重要。CH的大小已被证明与较高的疾病风险相关，然而，影响CH大小的因素尚不清楚。此外，CH在长寿个体中的特征并没有得到很好的记录。2024年2月15日，海南医学院任瑞宝、蔡望伟及上海交通大学陈竺共同通讯在PNAS 上在线发表题为“The impact of age and number of mutations on the size of clonal hematopoiesis”的研究论文，该研究报告了长寿(年龄≥90岁)和普通(年龄60 ~ 89岁)老年群体中CH的深入分析。该研究利用靶向深度测序，发现CH的发生发展与年龄和衰老生物标志物的表达密切相关。长寿老人组CH发生率显著增高，TET2和ASXL1基因突变频率显著增高，提示一定程度的CH可能有利于延长寿命。有趣的是，CH的大小与年龄( 60~110岁)无显著相关性，也与衰老生物标志物的表达无显著相关性。相反，大的CH大小与每个个体的突变数量之间有很强的相关性。这些发现为CH提供了一个风险评估的生物标志物，同时也表明CH的演变除了受年龄的影响外，还受到其他因素的影响。造血干细胞( hematopoietic stem cells，HSCs )在衰老过程中逐渐丧失增殖潜能。同时，在自我更新过程中，HSCs不断积累DNA突变。HSCs的某些突变可引起增殖增加和分化异常。由体细胞驱动突变驱动的造血干细胞及其子代的克隆性扩增被称为克隆性造血( CH )。随着年龄的增长，CH越来越常见，被称为年龄相关性克隆性造血( age-related clone hematopoietic，ARCH )。血液中存在恶性肿瘤相关基因的体细胞突变，而无血液系统恶性肿瘤、发育不良或血细胞减少的证据，且变异等位基因频率( variant allele frequency，VAF )≥2 %，称为不确定潜能的克隆性造血( clone hematopoietic of uncertain potential，CHIP )。既往研究表明，CHIP的患病率随着年龄增加而稳步增加。常见的CHIP突变影响多个基因，如DNMT3A、TET2、PPM1D、TP53、STAT3、IDH1、IDH2和ASXL1，其中大多数已知与血液系统恶性肿瘤相关。这些突变基因可归类为表观遗传调控因子、剪接因子、DNA损伤应答因子和造血转录因子。除年龄外，CHIP的发生发展还受到炎症、癌症相关治疗、吸烟、遗传因素等因素的影响。CHIP与血液系统恶性肿瘤如急性髓系白血病( acute myeloid leukemia，AML )、未明确意义的克隆性血细胞减少症、骨髓增生异常综合征和非血液系统疾病如心血管疾病、实体肿瘤和自身免疫性疾病的风险增加有关，以及总死亡率增加。CHIP还可以在体内激发炎症反应，并对这种炎症环境表现出强大的耐受性，增强CH的适应性，并增加脓毒症、严重冠状病毒感染( COVID-19 )和其他感染的风险。Setd2在自身免疫性疾病中表达减少（Credit: PNAS）并非所有的CH都会演变为血液系统恶性肿瘤或其他疾病。因此，CH的风险评估在疾病预防和临床实践中至关重要。研究表明，CH的进化受到突变类型和非突变相关因素的共同影响。研究还发现，CH的大小与疾病进展和预后相关，较大的克隆与较高的疾病风险相关。既往研究发现，高VAF (≥10 % )的个体发生肺癌、痛风、主要不良心脏事件( major adverse cardiac events，MACE )的风险显著增加。CH的大小也被纳入预测髓系恶性肿瘤的CH风险评分中。然而，影响CH大小的因素及其潜在的分子机制。然而，影响CH大小的因素及其潜在的分子机制尚不清楚。体细胞突变驱动的克隆扩增不仅发生在造血系统，而且在全身正常组织中也普遍发生。虽然某些克隆性扩张可以演变成癌症和/或促进其他疾病的发展，但某些克隆性扩张也可能在某些状态下通过对抗压力和老化条件而发挥有益的稳态作用。随着年龄的增长，HSCs的造血能力逐渐下降，这种变化在70岁以后更加明显。虽然CH在各年龄段人群中均有检出，但在长寿人群( 90岁及以上)中尚未进行系统研究。基于此，该研究比较了长寿(年龄≥90岁)和普通(年龄60 ~ 89岁)老年组的CH，发现长寿老年组的CH患病率显著升高，TET2和ASXL1突变显著增加。出乎意料的是，在60到110岁的范围内，CH的大小与年龄没有显著的相关性，也与衰老标志物的表达没有显著的相关性。相反，CH的大小与每个个体的突变数量之间存在显著的相关性。这些发现为CH的风险评估提供了生物标志物，并表明CH的演变除受年龄影响外，还受其他因素的影响。原文链接https://doi-org.libproxy1.nus.edu.sg/10.1073/pnas.2319364121责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

临床研究

2024-03-07

·BioSpace

CERo Therapeutics, Inc. Announces Publication of Preclinical Research Supporting the Use of Its Clinical Candidate CER-1236 to Treat AML Patients

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Cero Therapeutics Holdings, Inc., (NASDAQ:CERO) ("CERo") an innovative immunotherapy company seeking to advance the next generation of engineered T cell therapeutics that employ phagocytic mechanisms today announced the publication in Clinical Cancer Research, a journal of the American Association for Cancer Research, a paper titled “Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia.” The paper details preclinical studies by CERo analyzing its lead clinical candidate CER-1236 in targeting Acute Myelogenous Leukemia (AML) tumor cells from human patients, and the candidate’s killing effects on these tumor cells. The results in the paper found that the target for CER-1236 is found in the large majority (83%) of leukemic cells extracted from the bone marrow from patients, and that more importantly CER-1236 effectively eliminated leukemic cells in the company’s experiments. Finally, the target for CER-1236 was found by CERo to be highly expressed and detectable across common AML genetic classification subtypes, including patient samples with adverse risk mutations in TP53, ASXL1 and RUNX1. “This new publication provides support for our plans to test CER-1236 in AML patients in our planned Phase I clinical trial, and moreover extends the scientific data we have produced showing the target for CER-1236 is present on tumor cells from diverse cancers, including ovarian, non-small cell lung cancer (NSCLC), and B cell malignancies,” said Daniel Corey M.D, Ph.D, CERo’s Founder and Chief Technology Officer. “We’re very pleased with this publication in Clinical Cancer Research supporting our near term plans to advance CER-1236 into the clinic. As we have previously reported, CERo plans to Investigational New Drug (IND) application in the first half of 2024, and is targeting initial treatment of AML patients as well as B Cell lymphoma patients before the end of the year,” said Brian G Atwood, CERo’s Chairman and Chief Executive Officer. About CERo Therapeutics, Inc. CERo is an innovative immunotherapy company advancing the development of next generation engineered T cell therapeutics for the treatment of cancer. Its proprietary approach to T cell engineering, which enables it to integrate certain desirable characteristics of both innate and adaptive immunity into a single therapeutic construct, is designed to engage the body’s full immune repertoire to achieve optimized cancer therapy. This novel cellular immunotherapy platform is expected to redirect patient-derived T cells to eliminate tumors by building in engulfment pathways that employ phagocytic mechanisms to destroy cancer cells, creating what CERo refers to as Chimeric Engulfment Receptor T cells ("CER-T"). CERo believes the differentiated activity of CER-T cells will afford them greater therapeutic application than currently approved chimeric antigen receptor ("CAR-T") cell therapy, as the use of CER-T may potentially span both hematological malignancies and solid tumors. CERo anticipates initiating clinical trials for its lead product candidate, CER-1236, in 2024 for hematological malignancies. Forward-Looking Statements This communication contains statements that are forward-looking and as such are not historical facts. This includes, without limitation, statements regarding the financial position, business strategy and the plans and objectives of management for future operations of CERo. These statements constitute projections, forecasts and forward-looking statements, and are not guarantees of performance. Such statements can be identified by the fact that they do not relate strictly to historical or current facts. When used in this communication, words such as “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “strive,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. When CERo discusses its strategies or plans, it is making projections, forecasts or forward-looking statements. Such statements are based on the beliefs of, as well as assumptions made by and information currently available to, CERo’s management. Actual results could differ from those implied by the forward-looking statements in this communication. Certain risks that could cause actual results to differ are set forth in CERo’s filings with the Securities and Exchange Commission, including its Current Report on Form 8-K, as amended, filed on February 27, 2024, and the documents incorporated by reference therein. The risks described in CERo’s filings with the Securities and Exchange Commission are not exhaustive. New risk factors emerge from time to time and it is not possible to predict all such risk factors, nor can CERo assess the impact of all such risk factors on its business, or the extent to which any factor or combination of factors may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements are not guarantees of performance. You should not put undue reliance on these statements, which speak only as of the date hereof. All forward-looking statements made by CERo or persons acting on its behalf are expressly qualified in their entirety by the foregoing cautionary statements. CERo undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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