Acta haematologica · 2026
Differentiation Therapy in Acute Myeloid Leukemia: Advances in Phenotypic Screening and CRISPR-Based Functional Genomics.
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Takahashi Shinichiro
Аннотация
BACKGROUND: Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous malignancy characterized by a differentiation block in myeloid progenitors. Although advances in molecular targeted therapies have improved outcomes in selected subgroups, long-term prognosis remains poor for many patients. Differentiation therapy, exemplified by the success of all-trans retinoic acid in acute promyelocytic leukemia (APL), represents an alternative therapeutic paradigm that aims to overcome the differentiation blockade rather than directly inducing cytotoxicity.
SUMMARY: This review summarizes recent advances in phenotypic screening and CRISPR-based functional genomics that have contributed to the discovery of novel differentiation-inducing strategies in AML. High-throughput phenotypic screening approaches using compound libraries, computational tools, and integrative transcriptomic analyses have identified several candidate differentiation inducers. For example, triciribine, an AKT inhibitor, has been identified as a differentiation-inducing compound in AML models. In parallel, CRISPR loss- and gain-of-function screens have uncovered multilayered regulatory networks governing AML differentiation, including transcriptional regulators (e.g., KAT6A), metabolic dependencies (e.g., NMNAT1, glucose transporter type 1), and post-transcriptional regulators (e.g., ZFP36L2, YTHDC1). Emerging computational approaches, such as the Lineage Maturation Index and single-cell data integration, further enhance target prioritization and improve the translational relevance of screening results. Despite these advances, differentiation therapy outside APL remains challenging due to partial maturation, context-dependent responses, and AML heterogeneity.
KEY MESSAGES: Recent advances in phenotypic screening and CRISPR-based functional genomics have expanded our understanding of the molecular mechanisms governing AML differentiation and have revealed novel therapeutic vulnerabilities. Integration of these discovery platforms with computational and single-cell approaches may facilitate the development of differentiation-based strategies for a broader spectrum of AML patients.
SUMMARY: This review summarizes recent advances in phenotypic screening and CRISPR-based functional genomics that have contributed to the discovery of novel differentiation-inducing strategies in AML. High-throughput phenotypic screening approaches using compound libraries, computational tools, and integrative transcriptomic analyses have identified several candidate differentiation inducers. For example, triciribine, an AKT inhibitor, has been identified as a differentiation-inducing compound in AML models. In parallel, CRISPR loss- and gain-of-function screens have uncovered multilayered regulatory networks governing AML differentiation, including transcriptional regulators (e.g., KAT6A), metabolic dependencies (e.g., NMNAT1, glucose transporter type 1), and post-transcriptional regulators (e.g., ZFP36L2, YTHDC1). Emerging computational approaches, such as the Lineage Maturation Index and single-cell data integration, further enhance target prioritization and improve the translational relevance of screening results. Despite these advances, differentiation therapy outside APL remains challenging due to partial maturation, context-dependent responses, and AML heterogeneity.
KEY MESSAGES: Recent advances in phenotypic screening and CRISPR-based functional genomics have expanded our understanding of the molecular mechanisms governing AML differentiation and have revealed novel therapeutic vulnerabilities. Integration of these discovery platforms with computational and single-cell approaches may facilitate the development of differentiation-based strategies for a broader spectrum of AML patients.