Bueno Maura Lima Pereira, Saad Sara Teresinha Olalla, Roversi Fernanda Marconi
Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro-UNICAMP, Rua Carlos Chagas, 480 - Cidade Universitária Zeferino Vaz - Barão Geraldo, Campinas, São Paulo, 13083-878, Brazil.
Department of Surgery Division of Transplantation, Emory University, Atlanta, GA, USA.
J Cell Commun Signal. 2023 Dec;17(4):1487-1499. doi: 10.1007/s12079-023-00773-8. Epub 2023 Jun 13.
The bone marrow (BM) microenvironment (niche) is abnormally altered in acute myeloid leukemia (AML), leading to deficient secretion of proteins, soluble factors, and cytokines by mesenchymal stromal cells (MSC) that modifies the crosstalk between MSC and hematopoietic cells. We focused on a WNT gene/protein family member, WNT5A, which is downregulated in leukemia and correlated with disease progression and poor prognosis. We demonstrated that WNT5A protein upregulated the WNT non-canonical pathway only in leukemic cells, without modulating normal cell behavior. We also introduced a novel WNT5A-mimicking compound, Foxy-5. Our results showed reduction of crucial biological functions that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy, as well as G0/G1 cell cycle arrest. Additionally, Foxy-5 induced early-stage macrophage cell differentiation, a crucial process during leukemia development. At a molecular level, Foxy-5 led to the downregulation of two overexpressed leukemia pathways, PI3K and MAPK, which resulted in a disarrangement of actin polymerization with consequent impairment of CXCL12-induced chemotaxis. Notably, in a novel tri-dimensional bone marrow-mimicking model, Foxy-5 led to reduced leukemia cell growth and similar results were observed in a xenograft in vivo model. Overall, our findings highlight the pivotal role of WNT5A in leukemia and demonstrate that Foxy-5 acts as a specific antineoplastic agent in leukemia, counterbalancing several leukemic oncogenic processes related to the crosstalk in the bone marrow niche, and represents a promising therapeutic option for AML. WNT5A, a WNT gene/protein family member, is naturally secreted by mesenchymal stromal cells and contributes to the maintenance of the bone marrow microenvironment. WNT5A downregulation is correlated with disease progression and poor prognosis. The treatment with Foxy-5, a WNT5A mimetizing compound, counterbalanced several leukemogenic processes that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy and disruption of PI3K and MAPK signaling pathways.
急性髓系白血病（AML）中骨髓（BM）微环境（生态位）发生异常改变，导致间充质基质细胞（MSC）分泌的蛋白质、可溶性因子和细胞因子不足，从而改变了MSC与造血细胞之间的相互作用。我们聚焦于WNT基因/蛋白家族成员WNT5A，其在白血病中表达下调，并与疾病进展和不良预后相关。我们证明WNT5A蛋白仅在白血病细胞中上调WNT非经典途径，而不调节正常细胞行为。我们还引入了一种新型的模拟WNT5A的化合物Foxy-5。我们的结果显示，白血病细胞中上调的关键生物学功能有所降低，包括活性氧生成、细胞增殖和自噬，以及G0/G1细胞周期阻滞。此外，Foxy-5诱导早期巨噬细胞分化，这是白血病发展过程中的一个关键过程。在分子水平上，Foxy-5导致两条过表达的白血病途径PI3K和MAPK下调，导致肌动蛋白聚合紊乱，进而损害CXCL12诱导的趋化作用。值得注意的是，在一种新型的三维骨髓模拟模型中，Foxy-5导致白血病细胞生长减少，在体内异种移植模型中也观察到了类似结果。总体而言，我们的研究结果突出了WNT5A在白血病中的关键作用，并证明Foxy-5在白血病中作为一种特异性抗肿瘤药物，可抵消与骨髓生态位相互作用相关的几种白血病致癌过程，是AML一种有前景的治疗选择。WNT5A是WNT基因/蛋白家族成员，由间充质基质细胞自然分泌，有助于维持骨髓微环境。WNT5A下调与疾病进展和不良预后相关。用模拟WNT5A的化合物Foxy-5进行治疗，可抵消白血病细胞中上调的几种白血病发生过程，包括活性氧生成、细胞增殖和自噬以及PI3K和MAPK信号通路的破坏。
