Cytogenetically cryptic AML1-ETO and CBFbeta-MYH11 gene rearrangements: incidence in 412 cases of acute myeloid leukaemia

Abstract

The rearrangements t(8;21)(q22;22) and inv(16)(p13q22) are two of the most frequently seen in acute myeloid leukaemia (AML), accounting for 8% and 4% of cases respectively. Detection of these abnormalities is important for disease management as both are associated with good responses to conventional chemotherapy and prolonged disease-free survival. Recent reports using reverse transcriptase polymerase chain reaction (RT-PCR) suggest that significant proportions of AML cases without a visible t(8;21) or inv(16) show expression of an abnormal fusion gene transcript and, consequently, they could not be detected using conventional cytogenetic analysis alone. We present here a four centre study involving 412 cases of AML screened using both standard cytogenetics and RT-PCR for AML1-ETO and CBF beta-MYH11. We detected a cytogenetic t(8;21) in 31 out of 412 (7.5%) cases and an inv(16) or t(16;16) variant in 27 out of 412 (6.6%) cases. RT-PCR detected only two cases (0.5%) of cryptic t(8;21) and no instances of cryptic inv(16). Both cryptic t(8;21) cases had the classic M2 FAB morphology for this type of disease. Our data concur with the established FAB type distribution of the rearrangements and indicate that cryptic t(8;21) and inv(16) may be much less frequent than reported elsewhere.

Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program

“…166 The inv(16)-positive AMLs are included with those with t(8;21) translocation in a group generally referred to as 'core binding factor' (CBF) leukemias, as both are characterized by rearrangements of genes that code for components of the heterodimeric transcription factor CBF, which plays an essential role in hematopoiesis. 167 Inv(16) or the rarer t(16;16)(p13;q22) leads to fusion of the CBFB chain gene with the smooth muscle myosin heavy chain gene MYH11.…”

Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts

“…[1][2][3] Both types of disease are referred to collectively as core binding factor (CBF) leukemias resulting in the rearrangement, respectively, of alpha (CBFalfa or AML1) or beta (CBFbeta) subunits of the same transcription factor CBF which plays a key role in hematopoiesis. 4 In particular, genomic rearrangements in t (8;21) and inv (16) leukemias fuse CBFalfa with the gene encoding the ETO transcription factor and CBFbeta with the smooth muscle myosin heavy chain gene MYH11, respectively.…”

Screening for core binding factor gene rearrangements in acute myeloid leukemia

“…However, by analogy, analysis of 186 consecutive patients with PML-RAR␣-positive acute promyelocytic leukemia (APL) entered into the UK Medical Research Council (MRC) ATRA trial showed that 15% lack the t(15;17) due to cytogenetic failures (9%), insertions (4%) or more complex rearrangements (2%), 18 which is in accordance with data from the European Working Party. 19 As exemplified by the reports by Rowe et al 20 and Sarriera et al, 21 studies evaluating the role of molecular screening in AML to date have reported differing rates of detection of AML1-ETO and CBF␤-MYH11 in cases lacking the classic t(8;21) or inv(16)/t(16;16), respectively (see Tables 1 and 2 it should be born in mind that the studies detailed in Tables 1 and 2 are relatively small. This precludes reliable determination of the precise frequency of cryptic CBF gene rearrangements in AML and raises the possibility that the observed differences may in some instances have arisen by chance.…”

“…The studies reported by Rowe et al 20 and Sarriera et al 21 raise a number of key issues. In particular, they highlight the importance of confirming detection of leukemia-associated fusion genes revealed by RT-PCR screening with an independent technique.…”

“…A further potential influence upon reported CBF fusion gene frequencies relates to the age of the patient population subject to molecular screening, since it seems likely that cases harboring AML1-ETO or CBF␤-MYH11 in the absence of t(8;21) and inv(16)/t(16;16) will be more common in children and younger adults in whom at least 10-15% have CBF leukemia, 3,24,26 as opposed to older cohorts of patients in whom t(8;21) and inv (16) are relatively rare accounting for only 3% cases. 27 Therefore, the relatively low rates of cryptic AML1-ETO and CBF␤-MYH11 rearrangements reported by Rowe et al, 20 may relate to performance of cytogenetic analysis in specialist centers, combined with the inclusion of a significant proportion of elderly patients. Other aspects relating to the nature of the patient population also need to be taken into consideration in assessing the relative frequencies of CBF gene rearrangements.…”