SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-04-24 DOI:10.1002/ctm2.70163

Manuela Mancini, Sara De Santis, Cecilia Monaldi, Fausto Castagnetti, Miriam Iezza, Alessandra Iurlo, Daniele Cattaneo, Sara Galimberti, Marco Cerrano, Isabella Capodanno, Massimiliano Bonifacio, Maura Rossi, Claudio Agostinelli, Manja Meggendorfer, Torsten Haferlach, Michele Cavo, Gabriele Gugliotta, Simona Soverini

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Abstract

The SETD2 tumour suppressor encodes a histone methyltransferase that specifically trimethylates histone H3 on lysine 36 (H3K36me3), a key histone mark implicated in the maintenance of genomic integrity among other functions. We found that SETD2 protein deficiency, mirrored by H3K36me3 deficiency, is a nearly universal event in advanced-phase chronic myeloid leukemia (CML) patients. Similarly, K562 and KCL22 cell lines exhibited markedly reduced or undetectable SETD2/H3K36me3 levels, respectively. This resulted from altered SETD2 protein turnover rather than mutations or transcriptional downregulation, and proteasome inhibition led to the accumulation of hyper-ubiquitinated SETD2 and to H3K36me3 rescue suggesting that a functional SETD2 protein is produced but abnormally degraded. We demonstrated that phosphorylation by Aurora-A kinase and ubiquitination by MDM2 plays a key role in the proteasome-mediated degradation of SETD2. Moreover, we found that SETD2 and H3K36me3 loss impinges on the activation and proficiency of homologous recombination and mismatch repair. Finally, we showed that proteasome and Aurora-A kinase inhibitors, acting via SETD2/H3K36me3 rescue, are effective in inducing apoptosis and reducing clonogenic growth in cell lines and primary cells from advanced-phase patients. Taken together, our results point to SETD2/H3K36me3 deficiency as a mechanism, already identified by our group in systemic mastocytosis, that is reversible, druggable, and BCR::ABL1-independent, able to cooperate with BCR::ABL1 in driving genetic instability in CML.

Key Points

Virtually all CML patients in blast crisis display SETD2 loss of function.
SETD2 loss seems to be accomplished at the posttranslational level rather than being the result of genetic/genomic hits or transcriptional repression.
Phosphorylation by Aurora kinase A and ubiquitination by MDM2 contribute to SETD2 proteasome-mediated degradation in blast crisis CML patients.
Loss of SETD2 results in increased DNA damage.

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SETD2功能丧失是晚期慢性髓性白血病的复发事件，并导致基因组不稳定

SETD2肿瘤抑制因子编码一种组蛋白甲基转移酶，该酶特异性地将赖氨酸36上的组蛋白H3 （H3K36me3）三甲基化，这是维持基因组完整性和其他功能的关键组蛋白标记。我们发现SETD2蛋白缺乏（由H3K36me3缺陷反映）是晚期慢性髓性白血病（CML）患者中几乎普遍存在的事件。同样，K562和KCL22细胞系分别表现出明显降低或无法检测到SETD2/H3K36me3水平。这是由于SETD2蛋白转换的改变，而不是突变或转录下调，蛋白酶体抑制导致高泛素化SETD2的积累和H3K36me3的恢复，这表明产生了功能性SETD2蛋白，但异常降解。我们证明了Aurora-A激酶的磷酸化和MDM2的泛素化在蛋白酶体介导的SETD2降解中起着关键作用。此外，我们发现SETD2和H3K36me3的缺失会影响同源重组和错配修复的激活和熟练程度。最后，我们发现蛋白酶体和Aurora-A激酶抑制剂通过SETD2/H3K36me3拯救作用，在晚期患者的细胞系和原代细胞中有效诱导细胞凋亡和减少克隆生长。综上所述，我们的研究结果表明SETD2/H3K36me3缺陷是一种机制，我们的研究小组已经在系统性肥大细胞增多症中发现了这种机制，它是可逆的，可药物治疗的，并且不依赖于BCR::ABL1，能够与BCR::ABL1合作驱动CML的遗传不稳定性。几乎所有CML危象患者都表现出SETD2功能丧失。SETD2缺失似乎是在翻译后水平完成的，而不是遗传/基因组撞击或转录抑制的结果。极光激酶A的磷酸化和MDM2的泛素化有助于原细胞危重期CML患者SETD2蛋白酶体介导的降解。SETD2缺失导致DNA损伤增加。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.