Pp Pandolfi

Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia.

The acute promyelocytic leukaemia (APL) 15;17 translocation generates a PML/RAR alpha chimeric gene which is transcribed as a fusion PML/RAR alpha mRNA. Molecular studies on a large series of APLs revealed great heterogeneity of the PML/RAR alpha transcripts due to: (i) variable breaking of chromosome 15 within three PML breakpoint cluster regions (bcr1, bcr2 and bcr3), (ii) alternative splicings of the PML portion and (iii) alternative usage of two RAR alpha polyadenylation sites. Nucleotide sequence analysis predicted two types of proteins: multiple PML/RAR alpha and aberrant PML. The PML/RAR alpha proteins varied among bcr1, 2 and 3 APL cases and within single cases. The fusion proteins contained variable portions of the PML N terminus joined to the B‐F RAR alpha domains; the only PML region retained was the putative DNA binding domain. The aberrant PML proteins lacked the C terminus, which had been replaced by from two to ten amino acid residues from the RAR alpha sequence. Multiple PML/RAR alpha isoforms and aberrant PML proteins were found to coexist in all APLs. These findings indicate that two potential oncogenic proteins are generated by the t(15;17) and suggest that the PML activation pathway is altered in APLs.

Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) is characterised by a unique fusion transcript, PML/RAR alpha. We tested for this transcript in 35 APL patients who were in apparent remission after various treatments. 11 of 13 patients who tested positive 4 months after achieving remission were in relapse 1-4 months later. All 22 patients who tested negative at 4 months were disease-free after a further 3 months to five years. The test may therefore prove useful in determining the need for additional treatment during clinical remission.

Rearrangements of the RAR‐α gene in acute promyelocytic leukaemia:

Summary We have used genomic probes which specifically recognize DNA rearrangements of the RAR‐α locus on chromosome 17q21 in patients with acute promyelocytic leukaemia (APL) and acute myeloid leukaemia (AML) subtypes. Molecular data were examined in comparison with morphological and immunophenotypic characterization at diagnosis in 20 hypergranular FAB M3 cases, five microgranular APL (M3v), 51 non‐M3 AML and 12 myeloid CML blast crises.

Molecular Genetics of the t(15;17) Translocation in Acute Promyelocytic Leukemia

Acute Promyelocytic Leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) (FAB-M3 according to the French-American-British Cooperative Group). It is morphologically distinguished by the presence of hyper-granular leukemic blasts (Sultan et al. 1973; Bennett et al. 1976). The clinical propensity of APL patients to hemorrhage, the feature that first drew the attention to this type of acute leukemia, is thought to be due to the release of procoagulants by the granules in the malignant promyelocytes (Gralnick and Abrell 1973; Falanga et al. 1988). APL are cytogenetically distinguished by a balanced reciprocal chromosome 15; 17 translocation- t(15;17) (Rowley et al. 1977; Mitelman 1988). The high frequency (70 to 100% of cases) and the tumor-type specificity of the t(15;17) suggest that chromosome break-points affect DNA sequence that might be crucial in the pathogenesis of this malignancy.