Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms
Single-cell genomics reveals the genetic and molecular bases for escape from mutational epistasis in myeloid neoplasms
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DOI：
10.1182/blood.2020006868
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发表时间：
2020-09-24
期刊：
影响因子：
20.3
通讯作者：
Abdel-Wahab, Omar
中科院分区：
文献类型：
--
作者：
Taylor, Justin;Mi, Xiaoli;Abdel-Wahab, Omar
恶性血液病的大规模测序研究揭示了在高频率突变中显著的突变。上位性最显著的例子之一发生在RNA剪接因子的突变中。这些病变是骨髓肿瘤中最常见的改变之一，通常以相互排斥的方式发生，这一发现归因于它们的合成致死相互作用和/或会聚效应。然而，奇怪的是，已经观察到了多个伴随剪接因子突变的患者，这挑战了我们对血液恶性肿瘤中最常见的上位性例子之一的理解。在这项研究中，我们对携带双匕首2剪接因子突变的骨髓恶性肿瘤患者进行了大量和单细胞分析，以了解这些突变共存的频率和基础。尽管剪接因子突变在4231例患者中强烈相互排斥（q < .001），但0.85%的患者具有2个伴随的真正剪接因子突变，类似于50%的突变存在于相同的个体细胞中。然而，双突变患者的突变分布偏离单突变患者，选择最常见的等位基因SF 3B 1 K700 E和SRSF 2 P95 H/L/R，选择不太常见的等位基因，如SF 3B 1非K700 E突变、SRSF 2 P95的罕见氨基酸取代和U2 AF 1 S34/Q157组合突变。与最常见的等位基因相比，在具有双突变的那些中富集的SF 3B 1和SRSF 2等位基因对RNA剪接和/或结合的影响降低。此外，双U2 AF 1突变顺式发生，保留野生型等位基因。这些数据突出了等位基因特异性差异在调节剪接因子突变的分子效应以及它们彼此的共存/排他性方面至关重要。
Large-scale sequencing studies of hematologic malignancies have revealed notable epis-tasis among high-frequency mutations. One of the most striking examples of epistasis occurs for mutations in RNA splicing factors. These lesions are among the most common alterations in myeloid neoplasms and generally occur in a mutually exclusive manner, a finding attributed to their synthetic lethal interactions and/or convergent effects. Curiously, however, patients with multiple-concomitant splicing factor mutations have been observed, challenging our understanding of one of the most common examples of epistasis in hematologic malignancies. In this study, we performed bulk and single-cell analyses of patients with myeloid malignancy who were harboring double dagger 2 splicing factor mutations, to understand the frequency and basis for the coexistence of these mutations. Although mutations in splicing factors were strongly mutually exclusive across 4231 patients (q < .001), 0.85% harbored 2 concomitant bona fide splicing factor mutations, similar to 50% of which were present in the same individual cells. However, the distribution of mutations in patients with double mutations deviated from that in those with single mutations, with selection against the most common alleles, SF3B1K700E and SRSF2P95H/L/R, and selection for less common alleles, such as SF3B1 non-K700E mutations, rare amino acid substitutions at SRSF2P95, and combined U2AF1S34/Q157 mutations. SF3B1 and SRSF2 alleles enriched in those with double-mutations had reduced effects on RNA splicing and/or binding compared with the most common alleles. Moreover, dual U2AF1 mutations occurred in cis with preservation of the wild type allele. These data highlight allele-specific differences as critical in regulating the molecular effects of splicing factor mutations as well as their cooccurrences/exclusivities with one another.