Pirini Francesca, Ferrari Anna, Jandoubi Mouna, Azzali Irene, Angeli Davide, Mondrone Rossana, Bracci Chiara, Ruggieri Francesca, Martinelli Giovanni, Simonetti Giorgia
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy.
Biostatistics and Clinical Trials Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola (FC), Italy.
Cell Death Discov. 2025 Jul 2;11(1):301. doi: 10.1038/s41420-025-02573-y.
Polyamines, namely putrescine, spermidine and spermine, are involved in multiple molecular pathways through their ability to bind nucleic acids and modulate protein stability. Their intracellular level is regulated through biosynthesis, catabolism and uptake from the extracellular milieu and the disruption of their homeostasis contributes to a variety of human disorders including cancer, as mainly described in solid tumors. Recently, there is an increasing interest in understanding polyamine functions in acute leukemias, due to the linkage between leukemic gene drivers, polyamine metabolism alterations and epigenetic defects. In particular, polyamine involvement in the regulation of acetylation and methylation is clinically relevant since epigenetic drugs are currently the backbone of novel therapeutic combinations, especially in acute myeloid leukemia (AML). With the exception of methylthioadenosine phosphorylase (MTAP), the enzyme leading to methionine regeneration that is frequently deleted in acute lymphoblastic leukemia (ALL), genes involved in polyamine metabolism and the interconnected methionine and arginine pathways are rarely targets of genetic lesions in acute leukemias. Conversely, functional alterations, including elevated polyamine levels and deregulated activity of enzymes involved in their metabolism, have been recently reported in leukemic cells. Notably, the polyamine catabolic enzyme spermidine/spermine N1 acetyltransferase (SAT1) that is overexpressed in AML and associated with a myeloproliferative phenotype, is a tumor suppressor gene in ALL, suggesting diverse mechanisms of action across hematological malignancies according to the lineage commitment and the differentiation stage. In light of the promising results achieved in AML and ALL by selective targeting of protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A), two enzymes at the crossroad between polyamine metabolism and protein methylation, in this review we examine and discuss the role of polyamines in epigenetic regulation and other biological processes supporting leukemic cell survival, proliferation and differentiation, which provides the opportunity to discover additional polyamine-related targets and design novel therapeutic combinations.
多胺，即腐胺、亚精胺和精胺，通过其结合核酸和调节蛋白质稳定性的能力参与多种分子途径。它们的细胞内水平通过生物合成、分解代谢以及从细胞外环境摄取来调节，而其稳态的破坏会导致包括癌症在内的多种人类疾病，这在实体瘤中已有主要描述。最近，由于白血病基因驱动因素、多胺代谢改变和表观遗传缺陷之间的联系，人们对了解多胺在急性白血病中的功能越来越感兴趣。特别是，多胺参与乙酰化和甲基化的调节具有临床相关性，因为表观遗传药物目前是新型治疗组合的核心，尤其是在急性髓系白血病（AML）中。除了甲硫腺苷磷酸化酶（MTAP），该酶导致甲硫氨酸再生，在急性淋巴细胞白血病（ALL）中经常缺失，参与多胺代谢以及相互关联的甲硫氨酸和精氨酸途径的基因在急性白血病中很少成为遗传损伤的靶点。相反，最近在白血病细胞中报道了功能改变，包括多胺水平升高和参与其代谢的酶活性失调。值得注意的是，在AML中过表达并与骨髓增殖表型相关的多胺分解代谢酶亚精胺/精胺N1乙酰转移酶（SAT1），在ALL中是一个肿瘤抑制基因，这表明根据谱系承诺和分化阶段，多胺在血液系统恶性肿瘤中具有不同的作用机制。鉴于通过选择性靶向蛋白质精氨酸甲基转移酶5（PRMT5）和甲硫氨酸腺苷转移酶2A（MAT2A）在AML和ALL中取得了有前景的结果，这两种酶处于多胺代谢和蛋白质甲基化的交叉点，在本综述中，我们研究并讨论了多胺在表观遗传调节和支持白血病细胞存活、增殖和分化的其他生物学过程中的作用，这为发现其他与多胺相关的靶点和设计新型治疗组合提供了机会。
