小型抑制剂 WM-1119 可有效抑制 KAT6A 重组急性髓细胞性白血病,但不能抑制 KMT2A 重组急性髓细胞性白血病,尽管 KAT6 具有共同的遗传依赖性。

IF 29.5 1区 医学 Q1 HEMATOLOGY
Mathew Sheridan, Muhammad Ahmad Maqbool, Anne Largeot, Liam Clayfield, Jingru Xu, Natalia Moncaut, Robert Sellers, Jessica Whittle, Jerome Paggetti, Mudassar Iqbal, Romain Aucagne, Laurent Delva, Syed Murtuza Baker, Michael Lie-a-Ling, Valerie Kouskoff, Georges Lacaud
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引用次数: 0

摘要

表观遗传因子KAT6A(MOZ/MYST3)和KMT2A(MLL/MLL1)在正常造血过程中相互作用,调节祖细胞的自我更新。这两种蛋白在急性髓细胞性白血病中反复易位,导致这些恶性细胞的关键分化途径受损。我们评估了不同的 KAT6A 靶向治疗策略改变 KAT6A 和 KMT2A 重排急性髓细胞性白血病生长的潜力。我们采用细胞(流式细胞仪、集落测定、细胞生长)和分子(shRNA 敲除、CRISPR 敲除、大体和单细胞 RNA-seq、ChIP-seq)测定方法,研究了一流的 KAT6A 抑制剂 WM-1119 在 KAT6A 和 KMT2A 重排(KAT6Ar 和 KMT2Ar)AML 中的作用和潜在机制。我们还使用了两种新型遗传小鼠 KAT6A 模型与最常见的 KMT2Ar AML(KMT2A::MLLT3 AML)相结合。在这些小鼠模型中,KAT6A 或整个蛋白质的催化活性可被有条件地削弱或删除。通过这些模型,我们可以比较特异性 KAT6A KAT 活性抑制与完全删除整个蛋白的效果。最后,我们还在人类急性髓细胞白血病细胞系和原发性急性髓细胞白血病患者身上测试了这些治疗方法。我们发现,WM-1119 能完全抑制 KAT6Ar 细胞在体外的增殖和克隆生成潜能。WM-1119 治疗与骨髓分化程序的显著增加有关。治疗还在转录组水平上减少了干性和白血病通路,并导致融合蛋白与这些通路的关键调节因子失去结合。相比之下,我们的药理学和遗传学研究结果表明,KAT6A的催化活性在KMT2Ar致白血病中的作用较为有限,而靶向整个KAT6A蛋白则会显著影响小鼠KMT2A::MLLT3 AML的白血病潜能。我们的研究表明,抑制 KAT6A KAT 活性为 KAT6Ar AML 患者带来了令人信服的前景。相比之下,靶向降解 KAT6A(而不仅仅是其催化活性)可能是治疗 KMT2Ar AML 更为合适的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency
The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors’ self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.
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来源期刊
CiteScore
48.10
自引率
2.10%
发文量
169
审稿时长
6-12 weeks
期刊介绍: The Journal of Hematology & Oncology, an open-access journal, publishes high-quality research covering all aspects of hematology and oncology, including reviews and research highlights on "hot topics" by leading experts. Given the close relationship and rapid evolution of hematology and oncology, the journal aims to meet the demand for a dedicated platform for publishing discoveries from both fields. It serves as an international platform for sharing laboratory and clinical findings among laboratory scientists, physician scientists, hematologists, and oncologists in an open-access format. With a rapid turnaround time from submission to publication, the journal facilitates real-time sharing of knowledge and new successes.
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