A ß-catenin:MSI2 axis regulates the expression of LEF1 and subsequent human haematopoietic stem/progenitor cell proliferation
A ß-catenin:MSI2 axis regulates the expression of LEF1 and subsequent human haematopoietic stem/progenitor cell proliferation
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A-连环蛋白：MSI2 轴调节 LEF1 的表达和随后的人类造血干/祖细胞增殖
DOI：
10.1101/2024.01.28.577638
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Morgan R
中科院分区：
文献类型：
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作者：
Morgan R
Wnt/β-连环蛋白信号传导对于正常造血干/祖细胞（HSPC）生物学是重要的，并且与许多血液恶性肿瘤密切相关。中心介体β-连环蛋白是髓系肿瘤中有吸引力的治疗靶点，然而，由于对其在造血细胞中的分子相互作用的理解有限，靶向药物的设计受到阻碍。为了解决这一不足，我们最近在血液细胞中发表了第一个β-连环蛋白相互作用组（Morgan et al，2019），并鉴定了大量新的伴侣，其中包括RNA结合蛋白的显著富集（Wagstaff et al，2022），包括Musashi-2（MSI 2）。MSI 2与正常的HSC活性广泛相关，并且还促进侵袭性骨髓白血病，其表达导致生存率低下。MSI 2和Wnt信号传导之间的相互作用先前在造血背景下尚未报道。在这项研究中，我们确定了骨髓细胞系和原发性AML患者样本中MSI 2和β-连环蛋白之间的相互作用，其中蛋白质之间存在显著程度的相关性。我们证明了MSI 2可以通过调节LEF-1的表达和定位来影响Wnt信号输出（TCF/LEF活性），并且MSI 2可以进一步结合LEF 1转录物，这是由β-连环蛋白增强的相互作用。最后，我们表明MSI 2介导的HSPCs扩增可能部分通过LEF 1调控驱动。据我们所知，这是第一项证明造血细胞中MSI 2和β-连环蛋白之间相互作用的研究，并显示了β-连环蛋白与RBP合作控制HSPC增殖的潜力。最后，这些数据表明β-连环蛋白也可能在造血细胞中发挥关键的转录后功能（除了转录作用之外），这可能扩展到调节Wnt信号传导组分的表达。
Wnt/β-catenin signaling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in many hematological malignancies. The central mediator, β-catenin, is an attractive therapeutic target in myeloid neoplasms however, the design of targeted agents has been hampered by a limited understanding of its molecular interactions in hematopoietic cells. To address this shortfall, we recently published the first β-catenin interactome (Morgan et al, 2019) in haematological cells and identified a plethora of novel partners which included the significant enrichment of RNA binding proteins (Wagstaff et al, 2022), including Musashi-2 (MSI2). MSI2 has been extensively implicated in normal HSC activity and also promotes aggressive myeloid leukemias where its expression confers inferior survival. Interaction between MSI2 and Wnt signalling has not previously been reported in a hematopoietic context. In this study we identify an interaction between MSI2 and β-catenin in both myeloid cell lines and primary AML patient samples where there is a significant degree of correlation between the proteins. We demonstrate that MSI2 can impact Wnt signalling output (TCF/LEF activity) through modulating LEF-1 expression and localization, and that MSI2 can further bind LEF1 transcript, an interaction augmented by β-catenin. Finally, we show that MSI2 mediated expansion of HSPCs could be partly driven through LEF1 regulation. To our knowledge this is the first study to demonstrate an interaction between MSI2 and β-catenin in haematopoietic cells, and shows the potential for β-catenin to cooperate with RBPs to govern HSPC proliferation. Finally, these data indicate β-catenin may also serve critical post-transcriptional functions (in addition to transcriptional roles) in haematopoietic cells, which could extend to regulating expression of Wnt signalling components.