Elsevier Pathology

Clinical Pathology: Genetic Testing

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1023) A sample from an 11-year-old boy with a history of easy bruising, pancytopenia, and blasts on peripheral smear, was submitted for cytogenetic analysis. The karyotype analysis identified t(15;17)(q22;q21) (Figure 1); Fluorescence in situ hybridization (FISH) analysis using promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) gene probes showed rearrangement between these genes (Figure 2). Based on the karyotypic identification of 46,XY,t(15;17)(q22;q21) and the FISH identification of rearrangement between the PML and RARA loci, which statement is correct?

• The t(15;17)(q22;q21) translocation is confined to the FAB M3 morphologic subtype of acute promyelocytic leukemia (APL) with hyper-granular promyelocytic leukemic (PML) cells.

• The t(15;17) translocation is the sole cytogenetic abnormality in approximately 75% of cases. Trisomy 8 is the most common secondary change in 10% to 15% of cases.

• Despite the remarkable specificity of t(15;17)(q22;q21) in APL, this translocation can rarely present as a secondary change during chronic myelocytic leukemia in blast crisis.

• The t(15;17)(q22;q21) translocation results in the retinoic acid receptor α (RARA) gene on 17q22 fusing with a nuclear regulatory factor gene (i.e., the promyelocytic leukemia or PML gene) on 15q22, thereby giving rise to the PML/RARA fusion gene, which mediates the leukemogenic process.

• Acute promyelocytic leukemia (APL) with the t(15;17)(q22;q21) translocation exhibits a particular sensitivity to treatment with all-trans retinoic acid (ATRA), which acts as differentiating agent. Response of APL treated with ATRA and other combinations of drugs (e.g., anthracyclines, arsenic trioxide) is highest compared to any other acute myelocytic leukemia subsets.

• Variant translocations involving 17q22 (RARA) and NPM1 at 5q35, NUMA1 at 11q13, and ZBTB16 (previously known as PLZF) at 11q23 are seen in fewer than 2% cases of APL.

Mistry AR, Pedersen EW, Solomon E, et al: The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev 2003;17:71–97.

de Thé H, Chen Z: Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer 2010;10:775–783.

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