Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.
Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.
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DOI：
10.7554/elife.78136
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发表时间：
2022-08-30
期刊：
影响因子：
7.7
通讯作者：
Verma, Amit
中科院分区：
文献类型：
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作者：
Choudhary, Gaurav S.;Pellagatti, Andrea;Agianian, Bogos;Smith, Molly A.;Bhagat, Tushar D.;Gordon-Mitchell, Shanisha;Sahu, Srabani;Pandey, Sanjay;Shah, Nishi;Aluri, Srinivas;Aggarwal, Ritesh;Aminov, Sarah;Schwartz, Leya;Steeples, Violetta;Booher, Robert N.;Ramachandra, Murali;Samson, Maria;Carbajal, Milagros;Pradhan, Kith;Bowman, Teresa, V;Pillai, Manoj M.;Will, Britta;Wickrema, Amittha;Shastri, Aditi;Bradley, Robert K.;Martell, Robert E.;Steidl, Ulrich G.;Gavathiotis, Evripidis;Boultwood, Jacqueline;Starczynowski, Daniel T.;Verma, Amit
SF 3B 1剪接因子的突变常见于骨髓增生异常综合征（MDS）和急性髓性白血病（AML），但由错误剪接激活的特定致癌途径尚未完全阐明。炎症免疫途径已被证明在MDS的发病机制中起作用，尽管它们在剪接突变病例中激活的确切机制还不清楚。分析来自SF 3B 1突变体样品的RNA-seq数据，并确定白细胞介素-1受体相关激酶4（IRAK 4）亚型的功能作用。在MDS/AML的临床前模型中评价IRAK 4抑制的功效。SF 3B 1突变型MDS样本的RNA-seq剪接分析显示保留了IRAK 4的全长外显子6，IRAK 4是一种将Myddosome与炎性NF-κ B激活联系起来的关键下游介质。外显子6保留导致更长的同种型，编码包含整个死亡结构域和激酶结构域的蛋白质（IRAK 4-long），导致NF-κ B的最大活化。具有野生型SF 3B 1的细胞含有较小的IRAK 4同种型，其靶向蛋白酶体降解。IRAK 4-long在SF 3B 1突变细胞中的表达诱导TRAF 6活化，导致CDK 2的K63连接的泛素化，与造血分化的阻断相关。用CA-4948抑制IRAK 4导致NF-kB活化、炎性细胞因子产生减少、体外髓样分化增强和异种移植模型中白血病生长减少。SF 3B 1突变导致AML/MDS模型中治疗靶向的、更长的致癌IRAK 4亚型的表达。这项工作得到了辛辛那提儿童医院研究基金会、白血病淋巴瘤协会和国家卫生研究所（R35 HL 135787、RO 1HL 11103、RO 1DK 102759、RO 1HL 114582）、加布里埃尔天使癌症研究基金会和爱德华·埃文斯基金会的资助。AV由爱德华·埃文斯基金会、国家卫生研究所（R 01 HL 150832、R 01 HL 139487、R 01 CA 275007）、白血病和淋巴瘤协会、Curis和Jane和Myles P. Dempsey家庭的礼物支持。AP和JB由英国血液癌症（赠款13042和19004）支持。GC由NYSTEM的培训补助金支持。我们感谢帝国干细胞基金会通过纽约州卫生部合同C34874 GG提供的干细胞研究爱因斯坦培训计划对本研究的支持。MS由国家卫生研究培训和职业发展补助金研究所（F31 HL 132420）支持。基因包含了告诉细胞如何制造蛋白质的每一部分的代码块。在这些块之间是连接DNA的部分，当细胞准备使用它们的基因时，它们会被移除。科学家称这个过程为“拼接”。细胞可以以多种方式拼接某些基因，使它们能够从相同的遗传密码中产生不同的蛋白质。影响剪接过程的突变可以改变细胞制造蛋白质的方式，从而导致疾病。例如，骨髓增生异常综合征是一组血液癌症，通常由剪接蛋白（如SF 3B 1）突变引起。这种疾病阻止血细胞成熟，并导致异常炎症。到目前为止，剪接、血细胞不成熟、炎症和癌症之间的联系尚不清楚。为了了解更多，Choudhary，Pellagatti等人研究了骨髓增生异常综合征患者的拼接遗传密码。剪接蛋白SF 3B 1的突变改变了细胞剪接重要信号分子IRAK 4的方式。受影响的细胞削减了较少的遗传密码，并产生了这种信号蛋白的较长版本，称为IRAK 4-Long。这种改变的蛋白质激活炎症并阻止血细胞成熟。阻断IRAK 4-Long可以逆转这种效应。它还减少了携带受影响人类细胞的小鼠的肿瘤形成。用于阻断IRAK 4的分子CA-4948 -也称为Emavusertib -目前正在骨髓增生异常综合征和其他类型血癌的临床试验中进行评估。Choudhary，Pellagatti等人的工作可以帮助科学家设计基因测试来预测哪些患者可能从这种治疗中受益。
Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML. RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models. This work was supported by Cincinnati Children’s Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle’s Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420). Genes contain blocks of code that tell cells how to make each part of a protein. Between these blocks are sections of linking DNA, which cells remove when they are preparing to use their genes. Scientists call this process 'splicing'. Cells can splice some genes in more than one way, allowing them to make different proteins from the same genetic code. Mutations that affect the splicing process can change the way cells make their proteins, leading to disease. For example, the myelodysplastic syndromes are a group of blood cancers often caused by mutations in splicing proteins, such as SF3B1. The disorder stops blood cells from maturing and causes abnormal inflammation. So far, the link between splicing, blood cell immaturity, inflammation and cancer is not clear. To find out more, Choudhary, Pellagatti et al. looked at the spliced genetic code from people with myelodysplastic syndromes. Mutations in the splicing protein SF3B1 changed the way cells spliced an important signalling molecule known as IRAK4. Affected cells cut out less genetic code and made a longer version of this signalling protein, named IRAK4-Long. This altered protein activated inflammation and stopped blood cells from maturing. Blocking IRAK4-Long reversed the effects. It also reduced tumour formation in mice carrying affected human cells. The molecule used to block IRAK4, CA-4948 – also known as Emavusertib – is currently being evaluated in clinical trials for myelodysplastic syndromes and other types of blood cancer. The work of Choudhary, Pellagatti et al. could help scientists to design genetic tests to predict which patients might benefit from this treatment.