Genomic profile of radiation-induced early-onset mouse B-cell lymphoma recapitulates features of Philadelphia chromosome-like acute lymphoblastic leukemia in humans
Genomic profile of radiation-induced early-onset mouse B-cell lymphoma recapitulates features of Philadelphia chromosome-like acute lymphoblastic leukemia in humans
复制标题
辐射诱发的早发性小鼠 B 细胞淋巴瘤的基因组谱概括了人类费城染色体样急性淋巴细胞白血病的特征
DOI：
10.1093/carcin/bgac034
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发表时间：
2022
期刊：
影响因子：
4.7
通讯作者：
Kakinuma Shizuko
中科院分区：
文献类型：
--
作者：
Tachibana Hirotaka; Daino Kazuhiro; Ishikawa Atsuko; Morioka Takamitsu; Shang Yi; Ogawa Mari; Matsuura Akira; Shimada Yoshiya; Kakinuma Shizuko
流行病学研究表明，发生急性淋巴细胞白血病的风险与辐射有关。我们最近的研究揭示了辐射暴露后小鼠中前体B细胞（pB）淋巴瘤的早期诱导和风险增加。然而，辐射诱导的B细胞淋巴瘤的基因组景观仍然不清楚。为了确定小鼠中的相关遗传改变，对自发或γ照射后发生的早发性和迟发性B细胞淋巴瘤进行全外显子组测序。除了多个驱动突变外，数据显示，4号染色体的间质缺失，包括Pax 5和Jak 3的错义突变是辐射诱导的早发性B细胞淋巴瘤中独特的基因组改变。RNA测序显示，在早发性B细胞淋巴瘤中，pB细胞型基因表达谱不涉及已知的人类ALL融合基因。使用蛋白质毛细管电泳验证了Jak 3/Stat 5信号在早发性B细胞淋巴瘤中的激活。这些特征与费城染色体样ALL相似。我们的数据表明Pax 5功能缺失突变在启动B细胞白血病发生中的关键作用，加上Jak 3/Stat 5信号转导的激活，是辐射诱导的pB-ALL快速发展的基础。这些辐射诱发癌症的分子特征将为pB-ALL的风险评估和潜在靶向治疗提供信息。
Epidemiological studies have revealed a radiation-related increase in the risk of developing acute lymphoblastic leukemia (ALL). Our recent study revealed early induction and increased risk of precursor B-cell (pB) lymphomas in mice after radiation exposure. However, the genomic landscape of radiation-induced B-cell lymphomas remains unclear. To identify the relevant genetic alterations in mice, whole-exome sequencing was performed on both early-onset and late-onset B-cell lymphomas that developed spontaneously or after gamma-irradiation. In addition to multiple driver mutations, the data revealed that interstitial deletion of chromosome 4, includingPax5, and missense mutations inJak3are unique genomic alterations in radiation-induced, early-onset B-cell lymphomas. RNA sequencing revealed a pB-cell-type gene-expression profile with no involvement of known fusion genes for human ALLs in the early-onset B-cell lymphomas. Activation of Jak3/Stat5 signaling in early-onset B-cell lymphomas was validated using western capillary electrophoresis. Those features were similar to those of Philadelphia chromosome-like ALL. Our data suggest a critical role forPax5loss-of-function mutations in initiating B-cell leukemogenesis coupled with activation of Jak3/Stat5 signaling as a basis for the rapid development of radiation-induced pB-ALL. These molecular signatures for radiation-induced cancers will inform both risk assessment and potential targeted therapies for pB-ALL.