Protein biogenesis, maturation and degradation are tightly regulated processes that are governed by a complex network of signaling pathways. The endoplasmic reticulum (ER) is responsible for biosynthesis and maturation of secretory proteins. Circumstances that alter cellular protein homeostasis, determine accumulation of misfolded and unfolded proteins in the ER, a condition defined as ER stress. In case of stress, the ER activates an adaptive response called unfolded protein response (UPR), a series of pathways of major relevance for cancer biology. The UPR plays a preeminent role in adaptation of tumor cells to the harsh conditions that they experience, due to high rates of proliferation, metabolic abnormalities and hostile environment scarce in oxygen and nutrients. Furthermore, the UPR is among the main adaptive cell stress responses contributing to the development of resistance to drugs and chemotherapy. Clinical management of Acute Myeloid Leukemia (AML) has improved significantly in the last decade, thanks to development of molecular targeted therapies. However, the emergence of treatment-resistant clones renders the rate of AML cure dismal. Moreover, different cell populations that constitute the bone marrow niche recently emerged as a main determinant leading to drug resistance. Herein we summarize the most relevant literature regarding the role played by the UPR in expansion of AML and ability to develop drug resistance and we discuss different possible modalities to overturn this adaptive response against leukemia. To this aim, we also describe the interconnection of the UPR with other cellular stress responses regulating protein homeostasis. Finally, we review the newest findings about the crosstalk between AML cells and cells of the bone marrow niche, under physiological conditions and in response to therapies, discussing in particular the importance of the niche in supporting survival of AML cells by favoring protein homeostasis.

蛋白质的生物发生、成熟和降解是受到严格调控的过程，受复杂的信号通路网络控制。内质网 (ER) 负责分泌蛋白的生物合成和成熟。改变细胞蛋白质稳态的情况决定了错误折叠和未折叠蛋白质在 ER 中的积累，这种情况被定义为 ER 应激。在压力情况下，ER 会激活一种称为未折叠蛋白反应 (UPR) 的适应性反应，这是一系列与癌症生物学有重要关联的途径。由于高增殖率、代谢异常和氧气和营养物质稀缺的恶劣环境，UPR 在使肿瘤细胞适应它们所经历的严酷条件方面发挥着卓越的作用。此外，UPR 是导致对药物和化学疗法产生耐药性的主要适应性细胞应激反应之一。由于分子靶向治疗的发展，急性髓性白血病 (AML) 的临床管理在过去十年中有了显着改善。然而，耐药克隆的出现使得 AML 的治愈率令人沮丧。此外，构成骨髓生态位的不同细胞群最近成为导致耐药性的主要决定因素。在此，我们总结了关于 UPR 在扩大 AML 和产生耐药性能力方面所发挥作用的最相关文献，并讨论了不同的可能方式来推翻这种针对白血病的适应性反应。为此，我们还描述了 UPR 与调节蛋白质稳态的其他细胞应激反应的相互联系。最后，我们回顾了关于 AML 细胞和骨髓生态位细胞之间串扰的最新发现，在生理条件下和对治疗的反应，特别讨论了生态位通过有利于蛋白质稳态来支持 AML 细胞存活的重要性。