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

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Phenocopies in leukemia share characteristics with established genetic subtypes but lack their specific genetic alterations.
• RNA sequencing (RNAseq) classifiers identify phenocopy subtypes in acute lymphoblastic leukemia (ALL), including BCR::ABL1-like, ETV6::RUNX1-like, ZNF384-rearranged-like, and KMT2A-rearranged-like.
• Current classifications (WHO, ICC) have differing views on recognizing phenocopies as distinct entities.

Purpose of the Study:

• To explore the role of phenocopies in refining acute lymphoblastic leukemia (ALL) taxonomy and clinical management.
• To investigate the potential of phenocopies to improve risk stratification and guide targeted therapy selection.
• To highlight the challenges and future directions for the clinical adoption of phenocopy classification.

Main Methods:

• Utilized RNA sequencing (RNAseq) classifiers to identify and characterize ALL phenocopy subtypes.
• Integrated gene expression data with genotype, copy-number alterations, and measurable residual disease assessment for risk stratification.
• Reviewed current World Health Organization (WHO) and International Consensus Classifications (ICC) regarding leukemia taxonomy.

Main Results:

• RNAseq identified ALL phenocopies that replicate canonical expression patterns and may share drug vulnerabilities with known genetic subtypes.
• Phenocopies offer potential for refined risk stratification within "B-other" ALL.
• Convergent signaling pathways in phenocopies may allow access to pathway-directed therapies even without specific driver fusions.

Conclusions:

• Phenocopy identification is reshaping leukemia taxonomy and offers new avenues for personalized treatment strategies.
• Wider adoption of phenocopy classification is hindered by RNAseq accessibility, expertise, and current regulatory frameworks.
• Prospective studies are essential to validate the clinical utility of newly identified phenocopies and advance targeted therapy in ALL.