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Blood, 15 August 2000, Vol. 96, No. 4, pp. 1297-1308
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Characterization of acute promyelocytic leukemia cases lacking
the classic t(15;17): results of the European Working Party
David Grimwade,
Andrea Biondi,
Marie-Joëlle Mozziconacci,
Anne Hagemeijer,
Roland Berger,
Michael Neat,
Kathy Howe,
Nicole Dastugue,
Joop Jansen,
Isabelle Radford-Weiss,
Francesco Lo Coco,
Michel Lessard,
Jesus-Maria Hernandez,
Eric Delabesse,
David Head,
Vincenzo Liso,
Danielle Sainty,
Georges Flandrin,
Ellen Solomon,
Françoise Birg, and
Marina Lafage-Pochitaloff on behalf of
Groupe Français de Cytogénétique
Hématologique, Groupe
Français d'Hématologie
Cellulaire, UK Cancer Cytogenetics
Group, and BIOMED 1 European
Community-Concerted Action "Molecular Cytogenetic
Diagnosis in Haematological Malignancies"
From the Division of Medical and Molecular Genetics,
Guy's, King's, and St. Thomas' School of Medicine, London, United
Kingdom; Centro di Ricerca M. Tettamanti, Monza, Italy; Institut
Paoli-Calmettes, INSERM U119, IFR 57 and Université de la
Méditerranée, Marseille, France; Center for Human Genetics,
Leuven, Belgium; INSERM U434, Institut de Génétique
Moléculaire, Paris, France; St. Bartholomew's and the Royal
London School of Medicine, London, United Kingdom; Laboratoire de
Génétique des Hémopathies, CHU Purpan, Toulouse,
France; Institute for Hematology, Erasmus University, Rotterdam, The
Netherlands; Hôpital Necker Enfants Malades, Paris, France;
Dipartimento di Biotecnologie Cellulari ed Ematologia, Università
La Sapienza, Roma, Italy; Laboratoire de Cytogénétique, CHU
de Brest, France; Hospital Universitario de Salamanca, Salamanca,
Spain; St. Jude Children's Hospital, Memphis, TN; and Cattedra di
Ematologia i Policlinico di Bari, Bari, Italy.
Acute promyelocytic leukemia (APL) is typified by the t(15;17),
generating the PML-RAR fusion and predicting a
beneficial response to retinoids. However, a sizeable minority of APL
cases lack the classic t(15;17), prompting the establishment of the European Working Party to further characterize this group. Such cases
were referred to a workshop held in Monza, Italy and subjected to
morphologic, cytogenetic, and molecular review, yielding 60 evaluable
patients. In the majority (42 of 60), molecular analyses revealed underlying PML/RAR rearrangements due to
insertions (28 of 42) or more complex mechanisms, including 3-way and
simple variant translocations (14 of 42). Metaphase fluorescence in
situ hybridization (FISH) demonstrated that insertions most commonly led to formation of the PML-RAR fusion gene on 15q. In
11 of 60 workshop patients, PLZF/RAR rearrangements were
identified, including 2 patients lacking the t(11;17)(q23;q21). In one
case with a normal karyotype, FISH analysis revealed insertion of
RAR into 11q23, and PLZF-RAR was the sole
fusion gene formed. Two patients were found to have t(5;17), one with a
diffuse nuclear NPM staining pattern and with NPM-RAR
and RAR-NPM transcripts detected. In the other with an
unbalanced der(5)t(5;17)(q13;q21) and a nucleolar NPM localization
pattern, an NPM/RAR rearrangement was excluded, and FISH
revealed deletion of one RAR allele. In the remaining 5 workshop patients, no evidence was found for a rearrangement of
RAR, indicating that in rare instances, alternative mechanisms could mediate the differentiation block that typifies this
disease. This study highlights the importance of combining morphologic,
cytogenetic, and molecular analyses for optimal management of APL
patients and better understanding of the pathogenesis of the disease.
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