Phenocopies in acute lymphoblastic leukemia: Redefining leukemia subtypes in the transcriptomic era

Phenocopies are leukemias that mirror the transcriptional programs, signaling dependencies and often the clinical behavior of established genetic entities, yet lack their defining lesions. In acute lymphoblastic leukemia (ALL), RNA sequencing (RNAseq) classifiers identify phenocopy subtypes including BCR::ABL1-like, ETV6::RUNX1-like, ZNF384-rearranged-like and KMT2A-rearranged-like, which reproduce canonical expression patterns and may share drug vulnerabilities. Their emergence is reshaping taxonomy, but World Health Organization and International Consensus Classifications differ on which phenocopies merit entity status. Phenocopies can refine risk stratification within "B-other" ALL by integrating expression with genotype, copy-number alterations and measurable residual disease assessment. It may also broaden access to pathway-directed therapies (ABL, JAK-STAT, menin) for patients without sentinel fusions but with convergent circuitry. Adoption remains constrained by RNAseq availability, expertise and lesion-centric regulation. Prospective studies are needed to establish the clinical utility of newly described phenocopies, extending the advances made in subclassification and targeted treatment of BCR::ABL1-like ALL.