Characterization of acute promyelocytic leukemia cases lacking the classict(15;17): results of the European Working Party

Acute promyelocytic leukemia (APL) is typified by the t(15;17), generating the PML-RAR alpha-fusion and predicting a beneficial response to retinoids. However, a sizeable minority of APL cases lack the classic t(15;17), promp ting the establishment of the European Working Party to further characteriz e this group. Such cases were referred to a workshop held in Monza, Italy a nd subjected to morphologic, cytogenetic, and molecular review, yielding 60 evaluable patients. In the majority (42 of 60), molecular analyses reveale d underlying PML/RAR alpha rearrangements due to insertions(28 of 42) or mo re complex mechanisms, including 3-way and simple variant translocations (1 4 of 42). Metaphase fluorescence in situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RAR alpha fusion gene on 15q. In 11 of 60 workshop patients, PLZF/RAR alpha rearrangements w ere identified, including 2 patients lacking the t(11;17)(q23; q21). In one case with a normal karyotype, FISH analysis revealed insertion of RAR alph a into 11q23, and PLZF-RAR alpha was the sole fusion gene formed. Two patie nts were found to have t(5;17), one with a diffuse nuclear NPM staining pat tern and with NPM-RAR alpha and RAR alpha-NPM transcripts detected. In the other with an unbalanced der(5)t(5;17)(q13;q21) and a nucleolar NPM localiz ation pattern, an NPM/RAR alpha rearrangement was excluded, and FISH reveal ed deletion of one RAR alpha allele. In the remaining 5 workshop patients, no evidence was found for a rearrangement of RARa, indicating that in rare instances, alternative mechanisms could mediate the differentiation block t hat typifies this disease. This study highlights the importance of combinin g morphologic, cytogenetic, and molecular analyses for optimal management o f APL patients and better understanding of the pathogenesis of the disease. (Blood. 2000; 96:1297-1308) (C) 2000 by The American Society of Hematology .