当造血干细胞出现染色体和遗传异常、转化为白血病干细胞 (LSC) 并进一步获得驱动突变时，就会发生急性髓性白血病 (AML)。基因组分析的进展已经发现了许多与 AML 发展有关的新基因突变。最近的研究表明，具有 DDX41 和 CEBPA 等基因种系突变的个体在获得额外的体细胞突变后会发展为 AML，最新的 WHO 分类将具有此类突变的 AML 分为不同的疾病组。 LSC 受到与正常干细胞不同的代谢过程的调节，导致耐药性和复发。 LSC 依靠氧化磷酸化 (OXPHOS) 代谢来产生能量，而 Venetoclax 会抑制这一过程，从而影响 LSC。抗性 LSC 显示出增强的糖酵解，这表明同时针对 OXPHOS 和糖酵解至关重要。虽然 FLT3、BCL-2 和 IDH 抑制剂等靶向疗法已显示出疗效，但耐药性仍然是一个问题，这凸显了对新治疗策略的需求。 CAR-T 细胞疗法是一种新兴的免疫疗法，在靶向 CD123 和 CLL-1 方面显示出特别的前景，并且具有可接受的毒性。 CAR-T 细胞疗法和其他免疫疗法的未来发展预计将改善 AML 治疗结果。© 2024。日本血液学会。

Acute myeloid leukemia (AML) develops when hematopoietic stem cells acquire chromosomal and genetic abnormalities, transforming into leukemia stem cells (LSCs) and further gaining driver mutations. Advances in genomic analysis have identified numerous new gene mutations involved in AML development. Recent research has shown that individuals with germline mutations in genes like DDX41 and CEBPA develop AML upon acquiring additional somatic mutations, and the latest WHO classification separates AML with such mutations into distinct disease groups. LSCs are regulated by different metabolic processes than normal stem cells, contributing to drug resistance and relapse. LSCs rely on oxidative phosphorylation (OXPHOS) metabolism for energy production, and venetoclax inhibits this process, affecting LSCs. Resistant LSCs show enhanced glycolysis, which suggests that targeting both OXPHOS and glycolysis is crucial. While targeted therapies like FLT3, BCL-2, and IDH inhibitors have shown efficacy, resistance remains an issue, highlighting the need for new treatment strategies. CAR-T cell therapy is an emerging immunotherapy that shows particular promise for targeting CD123 and CLL-1, with acceptable toxicity. Future developments in CAR-T cell therapy and other immunotherapies are anticipated to improve AML treatment outcomes.© 2024. Japanese Society of Hematology.