From ALL to Myeloid and NK Malignancies: Operationalizing "ASNS-Low" for L-Asparaginase Repurposing and Combination Therapy.

L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7-associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies.