BACH2-mediated FOS confers cytarabine resistance via stromal microenvironment alterations in pediatric ALL.
BACH2-mediated FOS confers cytarabine resistance via stromal microenvironment alterations in pediatric ALL.
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BACH2 介导的 FOS 通过改变儿童 ALL 的基质微环境而赋予阿糖胞苷耐药性
DOI：
10.1111/cas.14792
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发表时间：
2021-03
期刊：
影响因子：
5.7
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Zhang H;Zhang R;Zheng X;Sun M;Fan J;Fang C;Tian X;Zheng H
急性淋巴细胞白血病（Acute lymphoblastic leukemia， ALL）是一种主要影响儿童的侵袭性血液学癌症。复发和化疗耐药导致治疗失败，强调需要改进治疗方法。BTB和CNC同源2 （BACH2）是一种淋巴特异性转录抑制因子，在淋巴瘤中被认为是一种肿瘤抑制因子，但对其在儿科ALL （p‐ALL）中的功能和调控网络知之甚少。在本研究中，我们发现新诊断时BACH2的异常表达不仅促进了p - ALL的风险分层，而且是早期治疗反应和临床结果的敏感预测因子。在ALL细胞中沉默BACH2可增加细胞增殖，加速细胞周期进程。BACH2阻断也促进细胞粘附骨髓基质细胞，并通过改变基质微环境赋予白血病细胞抗阿糖胞苷（Ara‐C）的特性。引人注目的是，我们发现与BACH2竞争的转录激活因子FOS是BACH2抑制的一个新的下游靶标。化合物阻断FOS可增强Ara - C治疗原发性p - ALL细胞和B - ALL前驱动的白血病异种移植物的效果，并延长载瘤小鼠的生存期。这些数据强调了BACH2 - FOS的相互连接网络，破坏该网络可以使当前的化疗更有效，并为克服p - ALL中Ara - C耐药性提供了一种有希望的治疗策略。我们发现与BACH2竞争的转录激活因子FOS是BACH2抑制的一个新的下游靶标。化合物阻断FOS增强了阿糖胞苷治疗原发性p - ALL细胞和B - ALL前驱动白血病的效果，延长了荷瘤小鼠的生存期。
Acute lymphoblastic leukemia (ALL) is an aggressive hematological cancer that mainly affects children. Relapse and chemoresistance result in treatment failure, underlining the need for improved therapies. BTB and CNC homology 2 (BACH2) is a lymphoid‐specific transcription repressor recognized as a tumor suppressor in lymphomas, but little is known about its function and regulatory network in pediatric ALL (p‐ALL). Herein, we found aberrant BACH2 expression at new diagnosis not only facilitated risk stratification of p‐ALL but also served as a sensitive predictor of early treatment response and clinical outcome. Silencing BACH2 in ALL cells increased cell proliferation and accelerated cell cycle progression. BACH2 blockade also promoted cell adhesion to bone marrow stromal cells and conferred cytarabine (Ara‐C)–resistant properties to leukemia cells by altering stromal microenvironment. Strikingly, we identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of Ara‐C treatment in both primary p‐ALL cells and pre‐B‐ALL–driven leukemia xenografts and prolonged the survival of tumor‐bearing mice. These data highlight an interconnected network of BACH2‐FOS, disruption of which could render current chemotherapies more effective and offer a promising therapeutic strategy to overcome Ara‐C resistance in p‐ALL. We identified FOS, a transcriptional activator competing with BACH2, as a novel downstream target repressed by BACH2. Blocking FOS by chemical compounds enhanced the effect of cytarabine treatment in primary p‐ALL cells and pre‐B‐ALL–driven leukemia xenografts and prolonged survival of tumor‐bearing mice.
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