A child presents with ALL. Cytogenetics show hyperdiploidy (>50 chromosomes). What is the prognostic implication and mechanism of improved drug response in hyperdiploid ALL?

• A Unfavorable — extra gene copies confer multi-drug resistance
• B Favorable — hyperdiploidy triggers constitutive p53-mediated apoptosis
• C Favorable — extra chromosomes increase methotrexate polyglutamate accumulation ✓
• D Neutral — ploidy does not affect drug sensitivity in ALL

Explanation

Hyperdiploidy (>50 chromosomes) in B-ALL is strongly favorable and is associated with excellent response to antimetabolite-based chemotherapy. The extra chromosomes, particularly trisomies of chromosomes 4, 10, and 17, increase the cellular accumulation of methotrexate polyglutamates, enhancing methotrexate cytotoxicity. This is one of the best-characterized mechanisms linking ploidy to drug sensitivity in pediatric ALL.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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