{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T06:55:17Z","timestamp":1783925717780,"version":"3.55.0"},"reference-count":55,"publisher":"S. Karger AG","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"},{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/karger.com\/pages\/terms-and-conditions"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Acta Haematol"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1159\/000551445","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:00:45Z","timestamp":1773421245000},"page":"1-22","source":"Crossref","is-referenced-by-count":1,"title":["Differentiation Therapy in Acute Myeloid Leukemia: Advances in Phenotypic Screening and CRISPR-Based Functional 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