Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.
Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.
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DOI：
10.1038/nm.4097
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发表时间：
2016-06
期刊：
影响因子：
82.9
通讯作者：
Abdel-Wahab O
中科院分区：
文献类型：
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作者：
Lee SC;Dvinge H;Kim E;Cho H;Micol JB;Chung YR;Durham BH;Yoshimi A;Kim YJ;Thomas M;Lobry C;Chen CW;Pastore A;Taylor J;Wang X;Krivtsov A;Armstrong SA;Palacino J;Buonamici S;Smith PG;Bradley RK;Abdel-Wahab O
剪接体基因突变常见于骨髓增生异常综合征(MDS)和急性髓系白血病(AML)患者。这些突变发生在高重复的氨基酸残基和干扰正常剪接位点和外显子识别。剪接体突变总是杂合性的，很少彼此共存，这表明细胞可能只容忍部分偏离正常剪接活性。为了验证这一假设，我们设计了在造血细胞中以可诱导的半合子方式表达SRSF2P95H突变的小鼠，这种突变通常发生在MDS和AML中。这些小鼠出现了致命的骨髓衰竭，表明SRSF2突变细胞依赖野生型SRSF2等位基因生存。在白血病的背景下，剪接体抑制剂E7107的治疗显著降低了白血病负担，特别是在同基因小鼠白血病和携带剪接体突变的患者来源的异种移植(PDX)AML中。虽然在体内暴露E7107导致广泛的内含子保留和盒式外显子跳跃，而无论SRSF2基因型，E7107治疗后剪接抑制的幅度在SRSF2突变型白血病比野生型白血病更大，这与E7107对这两种基因型的生存的不同影响是一致的。总之，这些数据提供了遗传学和药理学证据，表明与野生型白血病相比，具有剪接体突变的白血病在体内更容易受到额外的剪接干扰。剪接体功能的调节可能为MDS和AML患者的基因亚群提供一种新的治疗途径。
Mutations in spliceosomal genes are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations occur at highly recurrent amino acid residues and perturb normal splice site and exon recognition. Spliceosomal mutations are always heterozygous and rarely co-occur with one another, suggesting that cells may only tolerate a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice that express the SRSF2P95H mutation, which commonly occurs in MDS and AML, in an inducible hemizygous manner in hematopoietic cells. These mice developed lethal bone marrow failure, demonstrating that Srsf2-mutant cells depend on the wildtype Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 resulted in significant reductions in leukemic burden specifically in isogenic mouse leukemias and patient-derived xenograft (PDX) AMLs carrying spliceosomal mutations. While in vivo E7107 exposure resulted in widespread intron retention and cassette exon skipping regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutant versus wildtype leukemias, consistent with its differential effect on survival in these two genotypes. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal mutations are preferentially susceptible to additional splicing perturbations in vivo compared with wildtype counterparts. Modulation of spliceosome function may provide a novel therapeutic avenue in genetically defined subsets of MDS and AML patients.