RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS.
RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS.
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DOI：
10.1182/bloodadvances.2022007804
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发表时间：
2022-12-13
期刊：
影响因子：
7.5
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Huang, Yi-Jou;Chen, Jia-Yu;Yan, Ming;Davis, Amanda G.;Miyauchi, Sayuri;Chen, Liang;Hao, Yajing;Katz, Sigrid;Bejar, Rafael;Abdel-Wahab, Omar;Fu, Xiang-Dong;Zhang, Dong-Er
Srsf2 P95 H突变和Runx1缺陷的共存概括了在MDS中观察到的多系造血缺陷。RUNX1缺陷显著改变了整体剪接模式，并与Srsf2 P95 H突变协同影响DNA损伤反应基因。骨髓增生异常综合征（MDS）是一组异质性的血液恶性肿瘤，有进展为急性髓细胞白血病的倾向。在MDS患者中已发现多类基因的因果突变，一些患者携带1种以上的突变。有趣的是，双突变倾向于发生在不同的类别，而不是同一类基因，如转录因子RUNX1和剪接因子SRSF2中频繁的共现突变所示。这种原型双突变体提供了一个机会，了解他们的不同功能的转录和转录后调控可能会改变，共同促进MDS。在这里，我们报告了一个小鼠模型，其中Runx1基因敲除与Srsf2 P95 H突变相结合，导致多系造血缺陷。除了它们的累加和协同作用外，我们还意外地注意到特定造血祖细胞中单个突变的一定程度的拮抗活性。为了揭示该机制，我们进一步开发了一种使用人K562细胞的细胞模型，并在人和小鼠背景下进行了平行的基因表达和剪接分析。引人注目的是，尽管RUNX1缺陷导致单突变体和双突变体的转录改变，但它也诱导了全局剪接的显著变化，如突变体SRSF2所示，并且只有它们的组合诱导了选择性富集在DNA损伤反应和细胞周期检查点途径中的基因的错误剪接。总的来说，这些数据揭示了一个原型MDS相关的双突变体对RNA加工的趋同影响，并表明异常的DNA损伤修复和细胞周期调控对MDS的发展至关重要。
Coexistence of the Srsf2 P95H mutation and Runx1 deficiency recapitulates the multilineage hematopoietic defects observed in MDS. RUNX1 deficiency strikingly alters global splicing patterns and synergizes with the Srsf2 P95H mutation to affect DNA damage response genes. Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematologic malignancies with a propensity to progress to acute myeloid leukemia. Causal mutations in multiple classes of genes have been identified in patients with MDS with some patients harboring more than 1 mutation. Interestingly, double mutations tend to occur in different classes rather than the same class of genes, as exemplified by frequent cooccurring mutations in the transcription factor RUNX1 and the splicing factor SRSF2. This prototypic double mutant provides an opportunity to understand how their divergent functions in transcription and posttranscriptional regulation may be altered to jointly promote MDS. Here, we report a mouse model in which Runx1 knockout was combined with the Srsf2 P95H mutation to cause multilineage hematopoietic defects. Besides their additive and synergistic effects, we also unexpectedly noted a degree of antagonizing activity of single mutations in specific hematopoietic progenitors. To uncover the mechanism, we further developed a cellular model using human K562 cells and performed parallel gene expression and splicing analyses in both human and murine contexts. Strikingly, although RUNX1 deficiency was responsible for altered transcription in both single and double mutants, it also induced dramatic changes in global splicing, as seen with mutant SRSF2, and only their combination induced missplicing of genes selectively enriched in the DNA damage response and cell cycle checkpoint pathways. Collectively, these data reveal the convergent impact of a prototypic MDS-associated double mutant on RNA processing and suggest that aberrant DNA damage repair and cell cycle regulation critically contribute to MDS development.
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影响因子：
5.3
作者：
Komeno, Yukiko;Huang, Yi-Jou;Zhang, Dong-Er
通讯作者：
Zhang, Dong-Er
影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1261/rna.037879.112
发表时间：
2013-07
期刊：
RNA (New York, N.Y.)
影响因子：
--
作者：
Fukunaga J;Nomura Y;Tanaka Y;Amano R;Tanaka T;Nakamura Y;Kawai G;Sakamoto T;Kozu T
通讯作者：
Kozu T
DOI：
10.1073/pnas.1812669115
发表时间：
2018-10-30
影响因子：
11.1
作者：
Fei DL;Zhen T;Durham B;Ferrarone J;Zhang T;Garrett L;Yoshimi A;Abdel-Wahab O;Bradley RK;Liu P;Varmus H
通讯作者：
Varmus H
影响因子：
64.5
作者：
Ji X;Zhou Y;Pandit S;Huang J;Li H;Lin CY;Xiao R;Burge CB;Fu XD
通讯作者：
Fu XD