文章：

FBXO11是骨髓增生异常综合征向白血病转化中的一个候选肿瘤抑制因子

FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome

原文发布日期：2020-10-06

DOI: 10.1038/s41408-020-00362-7

类型: Article

开放获取: 是

英文摘要：

Myelodysplastic syndrome (MDS) is a heterogeneous myeloid malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of transformation to secondary acute myeloid leukemia (sAML). A number of genetic abnormalities have been identified in MDS and sAML, but sensitive sequencing methods can detect these mutations in nearly all healthy individuals by 60 years of age. To discover novel cellular pathways that accelerate MDS and sAML, we performed a CRISPR/Cas9 screen in the human MDS-L cell line. We report here that loss of the F-Box protein FBXO11, a component of the SCF ubiquitin ligase complex, confers cytokine independent growth to MDS-L cells, suggesting a tumor suppressor role for FBXO11 in myeloid malignancies. Putative FBXO11 substrates are enriched for proteins with functions in RNA metabolism and, of note, spliceosome mutations that are commonly found in MDS/sAML are rare in patients with low FBXO11 expression. We also reveal that loss of FBXO11 leads to significant changes in transcriptional pathways influencing leukocyte proliferation, differentiation, and apoptosis. Last, we find that FBXO11 expression is reduced in patients with secondary AML. We conclude that loss of FBXO11 is a mechanism for disease transformation of MDS into AML, and may represent a future therapeutic target.
 

摘要翻译： 

骨髓增生异常综合征（MDS）是一种异质性髓系恶性肿瘤，其特征为血细胞形态学发育异常、无效克隆造血以及向继发性急性髓系白血病（sAML）转化的风险。虽然已在MDS和sAML中发现多种遗传异常，但敏感测序技术检测到几乎所有60岁健康个体也携带这些突变。为探索加速MDS和sAML进展的新细胞通路，我们在人MDS-L细胞系中进行了CRISPR/Cas9筛选实验。本研究报道，SCF泛素连接酶复合体组分F-Box蛋白FBXO11的缺失可赋予MDS-L细胞细胞因子非依赖性生长能力，提示FBXO11在髓系恶性肿瘤中具有肿瘤抑制功能。FBXO11的推定底物富集于RNA代谢相关蛋白，值得注意的是，在FBXO11低表达患者中，MDS/sAML常见的剪接体突变较为罕见。我们还发现FBXO11缺失会导致影响白细胞增殖、分化和凋亡的转录通路发生显著改变。最后，我们观察到继发性AML患者中FBXO11表达降低。结论认为，FBXO11缺失是MDS向AML转化的机制之一，可能成为未来治疗靶点。

原文链接：

FBXO11 is a candidate tumor suppressor in the leukemic transformation of myelodysplastic syndrome