NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.
NRAS和KRAS激活点突变存在于10-30%的髓系恶性肿瘤中，常与增殖性表型相关。根据热点突变的不同，RAS突变具有等位基因特异性的结构和生化特性，导致其生物学影响存在差异。鉴于其在多数髓系恶性肿瘤中呈亚克隆特性，其克隆结构以及与其他驱动基因改变的协同作用模式，可能对髓系恶性肿瘤的预后和治疗产生直接的因果影响。总体而言，RAS突变往往与慢性及急性髓系恶性肿瘤的不良临床结局相关。近期多个预后评分系统已将RAS突变状态纳入考量。虽然RAS突变并不总是独立预后因素，但会显著影响疾病进展和生存率。然而，其临床意义取决于突变类型、疾病背景及所采用的治疗方案。最新证据还表明，RAS突变会导致对靶向治疗（尤其是FLT3、IDH1/2或JAK2抑制剂）以及维奈托克-阿扎胞苷联合疗法的耐药性。针对RAS通路内多个环节（包括上游和下游组分）的新型治疗策略与联合方案研究，目前是该领域活跃的前沿方向。直接RAS抑制剂在实体瘤患者中取得的成功，为这类疗法在血液恶性肿瘤患者中的应用带来了新的希望。本综述重点阐述过去十年间关于髓系恶性肿瘤中RAS突变的关键认识，包括其发生率与分布特征、协同遗传事件、克隆结构与动态演变、预后意义以及治疗靶向策略。
肿瘤(癌症)患者之家