Acute myeloblastic leukaemias of FAB types M6 and M4, with cryptic PML/RARα fusion gene formation, relapsing as acute promyelocytic leukaemia M3

Abstract

Summary. Demonstration of either the translocation t(15;17)(q22;q21) or the fusion of PML and RARa genes is regarded as diagnostic for acute myeloid leukaemia (AML) of FAB type M3, but has occasionally been seen in other FAB types. We present two such cases. Case 1 presented with FAB type M6 and a complex karyotype involving chromosomes 1, 2, 11 and 17. Bone marrow relapse of FAB type M3 followed autologous bone marrow transplantation. Subsequent marrow dysplasia and an M6 relapse were accompanied by a new cytogenetic clone involving chromosomes X, 2, 4, 6, 7 and 16. Fluorescence in situ hybridization (FISH) of metaphase chromosomes at diagnosis showed insertion of material from chromosome 17 into a`normal' 15 with juxtaposition of PML and RARa . Case 2 presented as AML M4 and relapsed as M3. Cytogenetic analysis at diagnosis and in relapse showed 46,XY,t(15;17)(q22;q11),del (16)(q22). FISH analysis showed this to be a three-way translocation involving chromosomes 15, 16 and 17 again with juxtaposition of PML and RARa . Reverse transcription-polymerase chain reaction (RT-PCR) revealed PML/RARa fusion at diagnosis, in remission and in first relapse. These examples strengthen the case for RT-PCR screening of all AML patients for these fusion genes.Keywords: AML M3, AML M4, AML M6, APL, PML-RARa .Acute promyelocytic leukaemia (APL) accounts for 10% of all cases of acute myeloid leukaemia (AML) and is classified as FAB type M3 on the basis of morphological features, large hypergranular promyelocytes which may contain bundles of Auer rods (Bennett et al, 1976) and the presence of t(15;17)(q22;q21). This translocation results in the fusion of the retinoic acid receptor a (RARa ) and the promyelocytic leukaemia (PML) genes located at 17q21 and 15q22 respectively (Borrow et al, 1992). Studies have shown that the t(15;17) is not detected by conventional cytogenetic analysis in up to 15% of cases of AML M3, due to either technical failure or the presence of cryptic insertion events leading to PML/RARa fusion (Grimwade et al, 1997;Burnett et al, 1999). Patients with AML M3 in whom the presence of the fusion genes PML/RARa or RARa /PML has been demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) , with or without detectable t(15;17), generally respond to differentiation therapy with all-trans retinoic acid (ATRA) and have a favourable prognosis when such treatment is combined with chemotherapy (Fenaux et al, 1999). The value of molecular analysis of all patients suspected of having APL is therefore established.It had been thought that t(15;17) or the associated fusion genes were exclusive to APL/AML M3. Recently, these have been described in AML with less differentiated FAB types M0, M1 and M2 (Aventin et al, 1998;Foley et al, 1998;Allford et al, 1999). We describe two further patients presenting with the PML-RARa fusion gene but with leukaemias affecting different myeloid lineages, namely erythrocytic AML M6 and myelomonocytic AML M4 leukaemias. Both patients relapsed with APL morphology. These finding...

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

“…[79][80][81][82] Nevertheless, these cases where tested were found to share the microparticulate PML nuclear staining pattern and ATRA sensitivity of patients with M3 morphology, further underlining the close relationship between the presence of the PML-RAR␣ fusion protein, disruption of PML nuclear bodies and the ATRA response. The occurrence of such cases has given rise to the proposal that all newly diagnosed cases of AML should be routinely screened for evidence of PML/RAR␣ rearrangements, with the rationale that additional patients would be identified for whom molecularly targeted therapies could be employed.…”

Mixed phenotype acute leukemia with PML-RARα positive: a case report and literature review

“…There is few cases of AML with PML-RARα fusion and t (15;17) that were neither immunophenotypically nor morphologically consistent with APL. (8) To sum up, MPAL T/myeloid (M5) with PML-RARα positivity and t (15;17) is indeed quite rare.…”

Mixed phenotype acute leukemia with PML-RARα positive: a case report and literature review

“…In general, PML-RARα fusion and t (15;17) are regarded as highly specific for acute promyelocytic leukemia (APL). There is few cases of AML with PML-RARα fusion and t (15;17) that were neither immunophenotypically nor morphologically consistent with APL [8]. To sum up, MPAL T/myeloid (M5) with PML-RARα positivity and t (15;17) is indeed quite rare.…”