Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.
Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.
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DOI：
10.1182/blood.2022018718
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发表时间：
2023-09-14
期刊：
影响因子：
20.3
通讯作者：
Starczynowski, Daniel T.
中科院分区：
文献类型：
--
作者：
Bennett, Joshua;Ishikawa, Chiharu;Agarwal, Puneet;Yeung, Jennifer;Sampson, Avery;Uible, Emma;Vick, Eric;Bolanos, Lyndsey C.;Hueneman, Kathleen;Wunderlich, Mark;Kolt, Amal;Choi, Kwangmin;Volk, Andrew;Greis, Kenneth D.;Rosenbaum, Jan;Hoyt, Scott B.;Thomas, Craig J.;Starczynowski, Daniel T.
IRAK 1和IRAK 4的共靶向需要通过诱导细胞分化在体外和体内最大限度地抑制LSPC功能。IRAK 1和IRAK 4在MDS/AML中的依赖性与其使用MyD 88的典型作用无关。先天性免疫信号转导失调是血液恶性肿瘤的标志。最近在骨髓增生异常综合征（MDS）和急性髓性白血病（AML）中颠覆异常先天免疫信号传导的治疗努力集中在激酶IRAK 4上。IRAK 4抑制剂在MDS和AML的临床前研究和临床试验中取得了有希望的（尽管是中等的）反应。对IRAK 4抑制剂的有限反应的潜在原因仍然未知。在这项研究中，我们揭示了抑制白血病细胞中的IRAK 4，通过其partial，IRAK 1来实现功能互补和补偿。使用遗传学方法，我们证明了共靶向IRAK 1和IRAK 4是抑制白血病干/祖细胞（LSPC）功能和诱导细胞系和患者源性细胞分化所必需的。虽然IRAK 1和IRAK 4被认为主要在近端衔接子MyD 88的下游发挥作用，但我们发现MDS/AML中的互补性和补偿性IRAK 1和IRAK 4依赖性通过非经典的MyD 88独立途径发生。基因组和蛋白质组学分析显示，IRAK 1和IRAK 4通过协调一系列通路，包括汇聚在多梳抑制复合物2复合物和JAK-STAT信号传导上的通路，保持MDS/AML LSPC的未分化状态。为了解释这些发现，我们实施了一种基于结构的设计，设计了一种有效的和选择性的双重IRAK 1和IRAK 4抑制剂KME-2780。与选择性IRAK 4抑制剂相比，当用KME-2780处理时，MDS/AML细胞系和患者来源的样品在异种移植物和体外研究中显示出对LSPC的显著抑制。我们的研究结果为共同靶向IRAK 1和IRAK 4治疗癌症（包括MDS/AML）提供了机制基础和理论依据。骨髓增生异常综合征和急性髓细胞白血病（MDS/AML）中的异常先天免疫信号提示了靶向治疗的新途径。激酶IRAK 4与MDS/AML中的免疫失调有关，但是，尽管早期临床试验令人鼓舞，但使用IRAK 4抑制剂的治疗作为单一疗法似乎是不够的。班尼特等人报道，IRAK 4抑制诱导代偿性IRAK 1上调，限制治疗功效;然而，同时靶向IRAK 1和IRAK 4导致体外研究和小鼠异种移植物中白血病干细胞的更大抑制。
Cotargeting of IRAK1 and IRAK4 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. The dependency of IRAK1 and IRAK4 in MDS/AML is independent of its canonical role using MyD88. Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. In this study, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. Although IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complementary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via noncanonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the polycomb repressive complex 2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in xenograft and in vitro studies when treated with KME-2780 as compared with selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for cotargeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML. Abnormal innate immune signaling in myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) suggests a novel pathway for targeted therapy. The kinase IRAK4 has been implicated in immune dysregulation in MDS/AML but, despite encouraging early clinical trials, therapy with an IRAK 4 inhibitor appears insufficient as monotherapy. Bennett et al report that IRAK4 inhibition induces compensatory IRAK1 upregulation, limiting therapeutic efficacy; however, simultaneous targeting of both IRAK1 and IRAK4 results in greater suppression of leukemic stem cells in in vitro studies and in mouse xenografts.
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