Molecular analysis of simple variant translocations in acute promyelocytic leukemia

Abstract

The primary cytogenetic abnormality in acute promyelocytic leukemia (APL; FAB M3) is a reciprocal translocation, t(15;17)(q22;q12), which serves to fuse the PML gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17. A PML-RARA fusion message transcribed from the der(15) is thought to mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3;15)(q21;q22) and t(X;15)(p11;q22), have previously been reported who lack cytogenetic involvement of chromosome 17, although their breakpoint positions on chromosome 15 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients, in which we wanted to determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the RARA locus has occurred instead. A cryptic involvement of RARA was demonstrated in both patients by a combination of Southern analysis, reverse transcription coupled to PCR (RT-PCR), and fluorescence in situ hybridization. The results indicate an absolute requirement for the rearrangement of the RARA gene in the pathogenesis of APL and underline the importance of RARA during normal myeloid differentiation.

Translocations of the RARα gene in acute promyelocytic leukemia

“…Therefore, it appears that in general expression of the reciprocal gene is not required for the development of APL. Consistently, there were cases of APL associated with non-reciprocal fusions of PML and RARa, which did not generate RARa ± PML fusion genes (Borrow et al, 1994;Hiorns et al, 1994). Furthermore, there are no dierences in ATRA sensitivities or clinical outcomes between patients who do or do not express the RARa ± PML transcripts (Li et al, 1997b).…”

Molecular cytogenetic characterization and clinical relevance of additional, complex and/or variant chromosome abnormalities in acute promyelocytic leukemia

“…Such cases have also been described by others. [30][31][32][33][34][35][36] These observations, together with the Leukemia fact that RAR␣-PML mRNA was only found in 70-80% patients, 8,37 confirm that PML-RAR␣ is the critical event in APL leukemogenesis. In addition to complex translocations, many chromosome abnormalities involving a single chromosome or chromosomal region were identified, such as addition, duplication, insertion and inversion, demonstrating that complicated cytogenetic changes may also contribute to the primary pathogenesis and/or disease evolution in APL.…”

Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia

“…33 Overall to date, 15 cases with the t(11;17)(q23;q21)/PLZF-RAR␣ fusion 33 formed as a result of insertion events, which may be cytogenetically cryptic, or more complex rearrangements. [33][34][35][36][37] In other cases, rearrangements of 17q21 lead to fusion of RAR␣ to alternative partner genes, ie PLZF (promyelocytic leukemia zinc finger), NPM (nucleophosmin), NuMA (nuclear mitotic apparatus) and STAT5b 38 associated with t(11;17)(q23;q21), t(5;17)(q35;q12-21), t(11;17)(q13;q21) and der(17) respectively. [38][39][40][41][42] It is now apparent that the nature of the fusion partner has a significant bearing upon disease characteristics, particularly the responsiveness to ATRA and arsenic trioxide.…”