PML/Rara and Rara/PML Chimeric Genes On Derivative Chromosome 17 In a Patient With Acute Promyelocytic Leukemia With Atypical t(15;17)(q11;q21)

Acute promyelocytic leukemia (APL) of the WHO classification is genetically characterized by the t(15;17)(q22;q21) chromosomal translocation involving the retinoic acid receptor alpha (RARA) located on band 17q21 and the promyelocytic leukemia gene (PML) on band 15q24 , leading to the PML/RARA fusion transcript, and by sensitivity of blast cells to all-trans retinoic acid or arsenic trioxide (ATO) targeted therapy. Although the vast majority of APL cases present with t(15;17)(q24;q21), formerly (q22;q21), a few patients have either simple or complex variants of this translocation involving chromosome 15, 17 and one or more other chromosomes. Analysis of these variant translocations is of great interest because they may mask a cryptic t(15;17) leading to misdiagnose a true APL as non APL-AML with other translocations involving RARA but not PML do exist, as mentioned in the WHO classification, and generally these cases do not respond to ATRA or ATO therapy and require more intensive chemotherapy. In these cases, the PML/RARA fusion gene can be identified by molecular analyses such as reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH).

29-year-old man presented with dizziness and tiredness. Physical examination: organomegaly was not observed. Peripheral blood: hemoglobin concentration, 71 g/L; platelet count, 10x10⁹/L white blood cell count (WBC) 0.5x10⁹/L. Bone marrow aspirate showed 56% blast cells with Auer rods. Coagulation tests were normal. Leukemic cells were CD13+, CD33+, CD34-, CD117+ and HLA-DR-. Cytogenetic analysis by G-banding performed in bone marrow metaphase cells afforded the following karyotype: 46,XY, t(15;17)(q11;q21) with derivative (der) (15) shorter and der(17) longer than in classical t(15;17)(q24;q21). PCR analysis of the PML/RAR fusion gene according to standard protocols disclosed the presence of the L isoform. FISH studies using dual color dual fusion probes (Vysis) covering the entire PML and RARA genes , showed a classical 2F1G1R (2 fusion, 1 green, 1 red) signal pattern on nuclei. However , on metaphases, we detected a normal PML (red) and RARA (green) signals on normal chromosome 15 and 17 respectively , but the two fusion signals were located on der(17). The patient was treated with IC-APL protocols (all-trans retinoic acid plus daunorubicin) and complete remission was achieved after induction therapy.

To explain the origin of the observed karyotype and molecular results, especially the double fusion signal on der(17), we propose two hypotheses: a classical t(15;17)(q24;q21) initially occurred leading to one fusion gene located on each derivative accompanied or followed either by a second translocation event implicating both derivative chromosomes with breakpoints located centromeric to the former breakpoint on der(15) and telomeric to the former breakpoint on der(17), or by an insertion of part of the der(15) containing the PML/RARA fusion gene into the der(17). Results obtained through FISH analysis support our first hypotheses. No differences in the clinical outcome between APL cases with classical t(15;17) and those with variant translocations leading to PML-RARA fusion gene have been reported. These results highlight the utility of combined cytogenetic, FISH and RT-PCR analyses to unveil the cases with variant or cryptic t(15;17). To our knowledge, this is the first report of an APL patient showing a variant t(15;17) involving only chromosomes 15 and 17 with two fusion signals on der(17).

No relevant conflicts of interest to declare.