Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore.
Gene. 2024 Nov 30;928:148761. doi: 10.1016/j.gene.2024.148761. Epub 2024 Jul 11.
Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.
白血病干细胞 (LSCs) 被广泛认为存在于特征明确的骨髓 (BM) 龛位中；然而，BM 龛位容纳 LSCs 的能力不足，很大一部分 LSCs 则维持在 BM 之外的区域。LSCs 这种与龛位无关的行为的分子基础仍然难以捉摸。在这里，我们通过整合素-α9 过表达（ITGA9 OE）模拟与龛位相互作用的状态，通过与可溶性配体骨桥蛋白 (OPN) 结合，来展示其在 LSCs 骨髓外维持中的关键作用。在易发生白血病的 Runx 缺陷小鼠中进行的逆转录病毒插入诱变鉴定出 ITGA9 OE 是一种新的致癌事件。ITGA9 OE 激活 Akt 和 p38MAPK 信号通路。随后，升高的 Myc 表达增强核糖体生物发生，以克服由先前存在的 Runx 改变引起的细胞完整性缺陷。最初在小鼠中发现的 Itga9-Myc 轴，在除 RUNX 白血病以外的多种人类急性髓系白血病 (AML) 亚型中得到了进一步证实。此外，在测试的 14 种已知 LSC 标志物中，ITGA9 被证明是具有最佳预后价值的功能性 LSC 标志物。值得注意的是，ITGA9 与可溶性 OPN 的结合，一种已知的抑制 HSC 激活的负调节剂，诱导 LSC 休眠，而 ITGA9-可溶性 OPN 相互作用的破坏导致细胞迅速增殖。这些发现表明，ITGA9 OE 以一种平衡的方式增加了活跃增殖的白血病细胞和休眠的 LSCs，从而维持了 LSCs。ITGA9 OE 将成为 AML 的一种新的治疗靶点。
