Emergence of clone with PHF6 nonsense mutation in chronic myelomonocytic leukemia at relapse after allogeneic HCT
Emergence of clone with PHF6 nonsense mutation in chronic myelomonocytic leukemia at relapse after allogeneic HCT
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DOI：
10.1007/s12185-021-03284-7
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发表时间：
2022-01
影响因子：
2.1
通讯作者：
Y. Akahoshi;H. Nakasone;Machiko Kusuda;K. Kameda;Yuhei Nakamura;Masakatsu Kawamura;J. Takeshita;S. Kawamura;Nozomu Yoshino;Yukiko Misaki;Kazuki Yoshimura;Shimpei Matsumi;Ayumi Gomyo;A. Tanihara;M. Tamaki;S. Kimura;S. Kako;Y. Kanda
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文献类型：
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作者：
Y. Akahoshi;H. Nakasone;Machiko Kusuda;K. Kameda;Yuhei Nakamura;Masakatsu Kawamura;J. Takeshita;S. Kawamura;Nozomu Yoshino;Yukiko Misaki;Kazuki Yoshimura;Shimpei Matsumi;Ayumi Gomyo;A. Tanihara;M. Tamaki;S. Kimura;S. Kako;Y. Kanda
疾病复发是异基因造血细胞移植（HCT）后治疗失败的主要原因，其机制尚不清楚。我们遇到了一个58岁的男子与慢性粒单核细胞白血病（CMML）复发后，半相合的HCT从他的女儿。对HCT和复发时采集的外周血样本进行分析，并通过流式细胞术分离通常在CMML中蓄积的CD 14 +/CD 16 −单核细胞。单核细胞的全外显子组测序揭示了HCT时CMML中的8种常见突变。此外，在HCT时未检测到的aPHF 6无义突变在复发时检测到。RNA测序无法检测到HLA或免疫检查点分子表达的变化，而这些分子是免疫逃避的重要机制。然而，基因集富集分析（GSEA）显示，TNF-α信号通路在复发时下调。复发时组蛋白H2 B120（H2 BK 120 ub）的泛素化水平显著降低，提示PHF 6的缺失可能通过减少H2 BK 120 ub下调TNF-α信号通路。该病例说明PHF 6缺失有助于克隆在应激条件下的竞争优势，并导致HCT后复发。
Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) and the mechanisms of relapse remain unclear. We encountered a 58-year-old man with chronic myelomonocytic leukemia (CMML) that relapsed after haploidentical HCT from his daughter. Peripheral blood samples collected at HCT and at relapse were analyzed, and CD14+/CD16−monocytes that typically accumulate in CMML were isolated by flow cytometry. Whole-exome sequencing of the monocytes revealed 8 common mutations in CMML at HCT. In addition, aPHF6nonsense mutation not detected at HCT was detected at relapse. RNA sequencing could not detect changes in expression of HLA or immune-checkpoint molecules, which are important mechanisms of immune evasion. However, gene set enrichment analysis (GSEA) revealed that a TNF-α signaling pathway was downregulated at relapse. Ubiquitination of histone H2B at lysine residue 120 (H2BK120ub) at relapse was significantly decreased at the protein level, indicating thatPHF6loss might downregulate a TNF-α signaling pathway by reduction of H2BK120ub. This case illustrates thatPHF6loss contributes to a competitive advantage for the clone under stress conditions and leads to relapse after HCT.