Amino acids in hematologic malignancies: Current status and future perspective

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TL;DR

This review examines how amino acids (glutamine, arginine, asparagine, cysteine, methionine, serine, and branched-chain amino acids) drive tumor development and therapy resistance in hematologic malignancies through mechanisms beyond metabolism, including signaling pathway regulation, epigenetic modulation, and tumor microenvironment remodeling. The authors highlight that targeting amino acid metabolism—via dietary starvation, enzymatic depletion, or transporter inhibition—represents a promising therapeutic strategy, with L-asparaginase serving as the most successful example in acute lymphoblastic leukemia. Clinically, several novel agents like CB-839 (glutaminase inhibitor) and ADI-PEG20 (arginine deiminase) have entered trials and shown encouraging results, particularly when combined with conventional chemotherapy to overcome drug resistance.

Full summary

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**Background:** Cancer cells undergo metabolic reprogramming to meet the heightened demands of rapid proliferation, invasion, and metastasis. While the Warburg effect describes preferential aerobic glycolysis, amino acids (AAs) have emerged as critical players in tumor biology beyond simple energy supply. AAs regulate key signaling pathways, modulate epigenetic factors, remodel the tumor microenvironment, and maintain redox homeostasis. In hematologic malignancies, targeting AA metabolism has already yielded clinical successes, most notably L-asparaginase in acute lymphoblastic leukemia (ALL). This review provides an updated overview of the mechanisms by which AAs facilitate tumor development and therapy resistance, and summarizes novel therapies targeting AA metabolism that are in preclinical and clinical development.

**Methods:** This is a narrative review synthesizing published literature on amino acid metabolism in hematologic malignancies. The authors organized the review by individual amino acids—glutamine, arginine, asparagine, cysteine, methionine, serine, and branched-chain amino acids (BCAAs)—discussing for each: (1) basic biochemistry and transport mechanisms, (2) roles in hematologic cancer biology, (3) therapeutic strategies targeting that amino acid, and (4) relevant preclinical and clinical trial data.

**Key Results:** - **Glutamine:** Enhanced glutaminolysis is a prominent feature of hematologic cancers. SLC1A5 (ASCT2) overexpression is observed in most leukemias, lymphomas, and myelomas and is associated with poor prognosis. The GLS inhibitor CB-839 (Telaglenastat) has shown preclinical synergy with proteasome inhibitors in multiple myeloma and with FLT3 inhibitors in FLT3-ITD-positive AML. In a phase II study (NCT0347993) of CB-839 (600 mg BID orally) plus azacitidine in advanced MDS, 62.5% (10/16) achieved marrow complete response and 31.3% (5/16) had stable disease. Grade III-IV adverse events included neutropenia (37.5%), thrombocytopenia (37.5%), and infections (43.7%). - **Arginine:** Over 70% of cancers are deficient in ASS1 and/or OTC, rendering them auxotrophic for arginine. ADI-PEG20 (pegylated arginine deiminase) showed a disease control rate of 42.9% in relapsed/refractory/poor-risk AML in a phase II study (NCT01910012), with minimal toxicity compared to chemotherapy. - **Asparagine:** L-asparaginase (L-ASNase) has been used clinically for over 40 years and is a cornerstone of multi-agent chemotherapy for ALL and NK/T-cell lymphoma. Resistance mechanisms include upregulation of ASNS expression (up to 7-fold), bone marrow MSC-mediated asparagine secretion, and autoantibody production. Novel formulations include PEGylated L-ASNase and Erwinia chrysanthemi L-ASNase. - **Cysteine:** AML leukemia stem cells (LSCs) are heavily dependent on cysteine metabolism for OXPHOS. Cysteine depletion via PEG-engineered cyst(e)inase doubled survival in aggressive CLL TCL1-Tg:p53−/− mice and selectively eliminated AML LSCs without affecting normal HSPCs. The xCT inhibitor sulfasalazine showed synergistic anti-leukemic effects with daunorubicin-cytarabine in NPM1-mutated AML. NAC supplementation reduced poor graft function after haploidentical HSCT in a phase III trial. - **Methionine:** ¹¹C-MET PET/CT showed higher sensitivity than ¹⁸F-FDG PET/CT for detecting myeloma lesions and differentiating CNS lymphoma from glioblastoma (ΔSUVmax < 1.17 achieved complete differentiation with no false results). The SAM decarboxylase inhibitor SAM486A showed an ORR of 18.9% in relapsed/refractory NHL in a phase II trial. Dietary methionine starvation impaired H3K36me3 and delayed AML progression in mouse models. - **Serine:** PHGDH inhibitor WQ-2101 increased cytarabine sensitivity in FLT3-ITD-driven AML. PSPH inhibition in T-ALL repressed proliferation and triggered apoptosis in vitro and in vivo. - **BCAAs:** BCAT1 overexpression in CML is associated with worse prognosis. Dietary BCAA starvation repressed LSC proliferation and self-renewal in xenogeneic transplantation models.

**Clinical Implications:** Targeting amino acid metabolism represents a viable therapeutic strategy for hematologic malignancies, with several agents already in clinical use or advanced trials. Key challenges include potential immunotoxicity (e.g., methionine starvation impairing T cell function), drug resistance mediated by bone marrow stromal cells providing amino acids to tumor cells, and limited half-life of depletion enzymes. Combination therapy—pairing AA starvation with conventional chemotherapy or targeted agents—appears most promising for overcoming resistance and improving outcomes. The field is moving toward more stable formulations (PEGylation, prodrugs like JHU083) and rational combination strategies based on identified metabolic dependencies.