人们普遍认为白血病干细胞（LSC）存在于特征明确的骨髓（BM）微环境中；然而，BM 生态位容纳 LSC 的能力不足，并且很大一部分 LSC 保留在 BM 以外的区域。 LSCs 这种与生态位无关的行为的分子基础仍然难以捉摸。在这里，我们发现整合素-α9 过表达（ITGA9 OE）通过与其可溶性骨桥蛋白（OPN）结合，在分子上模拟生态位相互作用状态，在 LSC 的髓外维持中发挥关键作用。对易患白血病的 Runx 缺陷小鼠进行逆转录病毒插入诱变，将 Itga9 OE 鉴定为一种新的致白血病事件。 Itga9 OE 激活 Akt 和 p38MAPK 信号通路。 Myc 表达升高随后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。 Itga9-Myc 轴最初在小鼠中发现，并在除 RUNX 白血病之外的多种人类急性髓系白血病 (AML) 亚型中得到进一步证实。此外，ITGA9 被证明是测试的 14 个已知 LSC 标记中具有最佳预后价值的功能性 LSC 标记。值得注意的是，ITGA9 与可溶性 OPN（一种已知的针对 HSC 激活的负调节因子）的结合诱导了 LSC 休眠，而 ITGA9-可溶性 OPN 相互作用的破坏导致细胞快速增殖。这些发现表明，ITGA9 OE 以均衡的方式增加活跃增殖的白血病细胞和休眠的 LSC，从而维持 LSC。 ITGA9 OE 将作为 AML 的新型治疗靶点。版权所有 © 2024 Elsevier B.V. 保留所有权利。

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 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.Copyright © 2024 Elsevier B.V. All rights reserved.