Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA.
Sci Adv. 2024 Aug 2;10(31):eadj3145. doi: 10.1126/sciadv.adj3145.
Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a proapoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2 dependent in but not in AML cells. Strikingly, in + cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment of the AKT/mTORC1 pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.
核仁磷酸蛋白（NPM1）的突变导致这种正常位于核仁的蛋白重新分布到细胞质中（NPM1c+）。尽管 NPM1 突变是细胞遗传学正常的成人急性髓细胞白血病（AML）中最常见的驱动突变，但 NPM1c+诱导白血病发生的机制仍不清楚。半胱天冬酶-2 是一种由核仁中的 NPM1 激活的促凋亡蛋白。在这里，我们表明 caspase-2 也被细胞质中的 NPM1c+激活，并且在 但不在 AML 细胞中，DNA 损伤诱导的细胞凋亡依赖于 caspase-2。引人注目的是，在 + 细胞中，caspase-2 的缺失导致明显的细胞周期停滞、分化和干细胞途径的下调，包括调节多能性的 AKT/mTORC1 途径的损伤，以及抑制 Rictor 的裂解。相比之下，缺乏 caspase-2 的 细胞在增殖、分化或转录谱方面差异很小。我们的研究结果表明，caspase-2 对于表达突变型 NPM1 的 AML 细胞的增殖和自我更新是必需的。本研究表明 caspase-2 是 NPM1c+功能的主要效应因子。
