重塑代谢脆弱性：氨基酸代谢途径在急性髓系白血病发病机制及靶向治疗中的新进展
Remodeling Metabolic Vulnerability: New Progress of Amino Acid Metabolism Pathways in the Pathogenesis and Targeted Therapy of Acute Myeloid Leukemia
摘要: 急性髓系白血病(Acute Myeloid Leukemia, AML)是一种具有高度临床和生物学异质性的造血系统恶性肿瘤。尽管以维奈克拉(Venetoclax)为代表的靶向药物在临床上取得了突破性进展，但白血病干细胞(Leukemia Stem Cells, LSCs)介导的复发和难治(R/R AML)仍是当前面临的最大挑战。近年来的高通量代谢组学研究揭示：“代谢重编程”不仅是AML细胞增殖的基本特征，更是其逃避化疗、适应低氧骨髓微环境及产生靶向药物耐药性的核心驱动力。其中，氨基酸不仅作为蛋白质合成的结构底物，更在维持三羧酸(TCA)循环、调控氧化还原稳态及重塑表观遗传图谱中发挥着多维作用。本文系统综述了谷氨酰胺、支链氨基酸、半胱氨酸及精氨酸等关键氨基酸代谢通路在AML发病机制中的最新研究进展，深入探讨了其与肿瘤微环境的代谢串扰，并全面总结了靶向氨基酸代谢在克服当前靶向治疗(如BCL-2抑制剂)耐药中的临床转化潜力。
Abstract: Acute Myeloid Leukemia (AML) is a hematological malignancy characterized by high clinical and biological heterogeneity. Although targeted therapies represented by Venetoclax have achieved breakthrough progress in clinical practice, relapsed and refractory AML (R/R AML) mediated by Leukemia Stem Cells (LSCs) remains the greatest challenge today. Recent high-throughput metabolomics studies have revealed that “metabolic reprogramming” is not only a fundamental feature of AML cell proliferation, but also the core driving force for evading chemotherapy, adapting to the hypoxic bone marrow microenvironment, and developing resistance to targeted drugs. Among them, amino acids serve not only as structural substrates for protein synthesis but also play multidimensional roles in maintaining the tricarboxylic acid (TCA) cycle, regulating redox homeostasis, and remodeling epigenetic landscapes. This article systematically reviews the latest research progress on key amino acid metabolic pathways—such as glutamine, branched-chain amino acids, cysteine, and arginine—in the pathogenesis of AML. It further explores their metabolic crosstalk with the tumor microenvironment and comprehensively summarizes the clinical translational potential of targeting amino acid metabolism to overcome resistance to current targeted therapies (e.g., BCL-2 inhibitors).
文章引用：王家莉, 陆天乐. 重塑代谢脆弱性：氨基酸代谢途径在急性髓系白血病发病机制及靶向治疗中的新进展[J]. 临床医学进展, 2026, 16(6): 646-652. https://doi.org/10.12677/acm.2026.1662262

参考文献

[1] DiNardo, C.D., Pratz, K.W., Letai, A., Jonas, B.A., Wei, A.H., Thirman, M., et al. (2018) Safety and Preliminary Efficacy of Venetoclax with Decitabine or Azacitidine in Elderly Patients with Previously Untreated Acute Myeloid Leukaemia: A Non-Randomised, Open-Label, Phase 1b Study. The Lancet Oncology, 19, 216-228. [Google Scholar] [CrossRef] [PubMed]
[2] Pei, S.S., Pollyea, D.A., Gustafson, A., et al. (2020) Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia. Cancer Discovery, 10, 536-551.
[3] Farge, T., Saland, E., de Toni, F., Aroua, N., Hosseini, M., Perry, R., et al. (2017) Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer Discovery, 7, 716-735. [Google Scholar] [CrossRef] [PubMed]
[4] Lagadinou, E.D., Sach, A., Callahan, K., Rossi, R.M., Neering, S.J., Minhajuddin, M., et al. (2013) BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells. Cell Stem Cell, 12, 329-341. [Google Scholar] [CrossRef] [PubMed]
[5] Ni, F., Yu, W., Li, Z., Graham, D.K., Jin, L., Kang, S., et al. (2019) Critical Role of ASCT2-Mediated Amino Acid Metabolism in Promoting Leukaemia Development and Progression. Nature Metabolism, 1, 390-403. [Google Scholar] [CrossRef] [PubMed]
[6] Willems, L., Jacque, N., Jacquel, A., Neveux, N., Trovati Maciel, T., Lambert, M., et al. (2013) Inhibiting Glutamine Uptake Represents an Attractive New Strategy for Treating Acute Myeloid Leukemia. Blood, 122, 3521-3532. [Google Scholar] [CrossRef] [PubMed]
[7] Emadi, A. (2015) Exploiting AML Vulnerability: Glutamine Dependency. Blood, 126, 1269-1270. [Google Scholar] [CrossRef] [PubMed]
[8] Gregory, M.A., Nemkov, T., Park, H.J., Zaberezhnyy, V., Gehrke, S., Adane, B., et al. (2019) Targeting Glutamine Metabolism and Redox State for Leukemia Therapy. Clinical Cancer Research, 25, 4079-4090. [Google Scholar] [CrossRef] [PubMed]
[9] Gallipoli, P., Giotopoulos, G., Tzelepis, K., Costa, A.S.H., Vohra, S., Medina-Perez, P., et al. (2018) Glutaminolysis Is a Metabolic Dependency in FLT3ITD Acute Myeloid Leukemia Unmasked by FLT3 Tyrosine Kinase Inhibition. Blood, 131, 1639-1653. [Google Scholar] [CrossRef] [PubMed]
[10] Matre, P., Velez, J., Jacamo, R., Qi, Y., Su, X., Cai, T., et al. (2016) Inhibiting Glutaminase in Acute Myeloid Leukemia: Metabolic Dependency of Selected AML Subtypes. Oncotarget, 7, 79722-79735. [Google Scholar] [CrossRef] [PubMed]
[11] Reitman, Z.J. and Yan, H. (2010) Isocitrate Dehydrogenase 1 and 2 Mutations in Cancer: Alterations at a Crossroads of Cellular Metabolism. JNCI Journal of the National Cancer Institute, 102, 932-941. [Google Scholar] [CrossRef] [PubMed]
[12] Jacque, N., Ronchetti, A.M., Larrue, C., Meunier, G., Birsen, R., Willems, L., et al. (2015) Targeting Glutaminolysis Has Antileukemic Activity in Acute Myeloid Leukemia and Synergizes with BCL-2 Inhibition. Blood, 126, 1346-1356. [Google Scholar] [CrossRef] [PubMed]
[13] Xiang, Y., Stine, Z.E., Xia, J., Lu, Y., O’Connor, R.S., Altman, B.J., et al. (2015) Targeted Inhibition of Tumor-Specific Glutaminase Diminishes Cell-Autonomous Tumorigenesis. Journal of Clinical Investigation, 125, 2293-2306. [Google Scholar] [CrossRef] [PubMed]
[14] Raffel, S., Falcone, M., Kneisel, N., Hansson, J., Wang, W., Lutz, C., et al. (2017) BCAT1 Restricts ΑKg Levels in AML Stem Cells Leading to IDHmut-Like DNA Hypermethylation. Nature, 551, 384-388. [Google Scholar] [CrossRef] [PubMed]
[15] Hattori, A., Tsunoda, M., Konuma, T., Kobayashi, M., Nagy, T., Glushka, J., et al. (2017) Cancer Progression by Reprogrammed BCAA Metabolism in Myeloid Leukaemia. Nature, 545, 500-504. [Google Scholar] [CrossRef] [PubMed]
[16] Jones, C.L., Stevens, B.M., D’Alessandro, A., Reisz, J.A., Culp-Hill, R., Nemkov, T., et al. (2018) Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells. Cancer Cell, 34, 724-740.e4. [Google Scholar] [CrossRef] [PubMed]
[17] Cunningham, A., Oudejans, L.L., Geugien, M., Pereira-Martins, D.A., Wierenga, A.T.J., Erdem, A., et al. (2024) The Nonessential Amino Acid Cysteine Is Required to Prevent Ferroptosis in Acute Myeloid Leukemia. Blood Advances, 8, 56-69. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, H.Y., Sun, C.J., Sun, Q., Li, Y., Zhou, C. and Sun, C.G. (2023) Susceptibility of Acute Myeloid Leukemia Cells to Ferroptosis and Evasion Strategies. Frontiers in Molecular Biosciences, 10, Article 1275774. [Google Scholar] [CrossRef] [PubMed]
[19] Miraki-Moud, F., Ghazaly, E., Ariza-McNaughton, L., Hodby, K.A., Clear, A., Anjos-Afonso, F., Liapis, K., Grantham, M., Sohrabi, F., Cavenagh, J., Bomalaski, J.S., Gribben, J.G., Szlosarek, P.W., Bonnet, D. and Taussig, D.C. (2015) Arginine Deprivation Using Pegylated Arginine Deiminase Has Activity against Primary Acute Myeloid Leukemia Cells in Vivo. Blood, 125, 4060-4068. [Google Scholar] [CrossRef] [PubMed]
[20] Changou, C.A., Chen, Y.R., Xing, L., Yen, Y., Chuang, F.Y., Cheng, R.H., Bold, R.J., Ann, D.K. and Kung, H.J. (2014) Arginine Starvation-Associated Atypical Cellular Death Involves Mitochondrial Dysfunction, Nuclear DNA Leakage, and Chromatin Autophagy. Proceedings of the National Academy of Sciences of the United States of America, 111, 14147-14152. [Google Scholar] [CrossRef] [PubMed]
[21] Miraki-Moud, F., Ghazaly, E., Ariza-McNaughton, L., Hodby, K.A., Clear, A., Anjos-Afonso, F., et al. (2015) Arginine Deprivation Using Pegylated Arginine Deiminase Has Activity against Primary Acute Myeloid Leukemia Cells in Vivo. Blood, 125, 4060-4068. [Google Scholar] [CrossRef] [PubMed]
[22] Mussai, F., De Santo, C., Abu-Dayyeh, I., Booth, S., Quek, L., McEwen-Smith, R.M., et al. (2013) Acute Myeloid Leukemia Creates an Arginase-Dependent Immunosuppressive Microenvironment. Blood, 122, 749-758. [Google Scholar] [CrossRef] [PubMed]
[23] Stevens, B.M., Jones, C.L., Pollyea, D.A., Culp-Hill, R., D’Alessandro, A., Winters, A., et al. (2020) Fatty Acid Metabolism Underlies Venetoclax Resistance in Acute Myeloid Leukemia Stem Cells. Nature Cancer, 1, 1176-1187. [Google Scholar] [CrossRef] [PubMed]
[24] Pollyea, D.A., Stevens, B.M., Jones, C.L., Winters, A., Pei, S., Minhajuddin, M., et al. (2018) Venetoclax with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Patients with Acute Myeloid Leukemia. Nature Medicine, 24, 1859-1866. [Google Scholar] [CrossRef] [PubMed]
[25] van Gastel, N., Spinelli, J.B., Sharda, A., Schajnovitz, A., Baryawno, N., Rhee, C., et al. (2020) Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance. SSRN Electronic Journal, 32, 391-403.e6. [Google Scholar] [CrossRef] 
[26] Škrtić, M., Sriskanthadevan, S., Jhas, B., Gebbia, M., Wang, X., Wang, Z., et al. (2011) Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer Cell, 20, 674-688. [Google Scholar] [CrossRef] [PubMed]
[27] Tabe, Y., Lorenzi, P.L. and Konopleva, M. (2019) Amino Acid Metabolism in Hematologic Malignancies and the Era of Targeted Therapy. Blood, 134, 1014-1023. [Google Scholar] [CrossRef] [PubMed]
[28] Jkreitz, J., Schönfeld, C., Seubert, M., et al. (2019) Metabolic Plasticities and Dependencies in Acute Myeloid Leukemia. Cancer Discovery, 9, 1598-1615.

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