Childhood acute lymphoblastic leukaemia with ider(21)(q10)t(12;21)(p12;q22): a new recurrent abnormality showing ETV6/CBFA2 fusion

Abstract

Summary. The cytogenetically unidentifiable t(12;21) (p12;q22), resulting in ETV6/CBFA2 fusion, is the most frequent chromosomal aberration in childhood acute lymphoblastic leukaemia (ALL). We report a variant, ider(21) (q10)t(12;21)(p12;q22), which was shown to contain double ETV6/CBFA2 fusions by fluorescence in situ hybridization. This is the second case of such an ider(21) in childhood ALL, suggesting that it is a new recurrent abnormality. Since the ider(21) is cytogenetically indistinguishable from i(21)(q10) and idic(21)(p11), changes associated with similar clinical features as the t(12;21), i.e. pre-B-cell ALL and age 1-10 years, we suggest that all ALL displaying these changes should be tested for ETV6/CBFA2 fusion transcript. Keywords: childhood ALL, cytogenetics, FISH, ETV6/CBFA2.The t(12;21)(p12;q22) is present in 20-30% of childhood acute lymphoblastic leukaemia (ALL), making it the single most frequent chromosomal abnormality in this setting (Romana et al, 1995b;Liang et al, 1996). The patients are usually between 1 and 10 years old, display a pre-B-cell ALL, and seem to have a favourable, or even excellent, prognosis (Shurtleff et al, 1995;Liang et al, 1996). Since the breakpoints at chromosomes 12 and 21 are located in similarly lightstaining telomeric bands, this translocation is unidentifiable with standard banding techniques. However, using fluorescence in situ hybridization (FISH) the aberration is readily seen. At the molecular level, the translocation has been shown to result in fusion between the ETV6 and CBFA2 genes (previously TEL and AML1, respectively) (Golub et al, 1995;Romana et al, 1995a).A 6-year-old boy was admitted to hospital due to pain in the legs and fever. Peripheral blood showed a white cell count of 3 : 2 × 10 9 /l, haemoglobin of 6 . 9 g/dl and thrombocytes of 52 × 10 9 /l. Hepatosplenomegaly was noted on clinical examination. Morphological and immunophenotypical bone marrow investigations revealed a pre-B-cell ALL of FAB L1/ L2 subtype. Cytogenetic studies showed a pseudodiploid karyotype: 46,XY,del(12)(p12),i(21)(q10).FISH was performed, as previously described (Andreasson et al, 1997), with whole chromosome painting (wcp) probes for chromosomes 12 and 21. This analysis not only verified the i(21q) but also disclosed a der(12) with chromosome 21 material at the end of the p-arm, suggesting a cryptic t(12;21). Further FISH experiments were performed with YAC probes 964c10 and 958b8, covering the ETV6 gene (Kobayashi et al, 1994) and cosmids 179a6, 163e7 and 244e8, specific for the same gene . CBFA2 rearrangement was detected with five overlapping YAC probes: 812f11, covering the CBFA2 breakpoint, 464h8 and 613e10 located telomeric, and 72h9 and 831b9 located centromeric to the breakpoint (Romana et al, 1995a). These analyses showed: (1) an ETV6/CBFA2 fusion at both arms of the isochromosome, consequently re-interpreted as ider(21)(q10)t(12;21)(p12;q22); (2) a reciprocal fusion at the der(12)t(12;21); and (3) no signal at the del(12)(p12), neither by YAC nor cosmid probe...

Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study

“…35 The fusion gene is duplicated in one patient in our series (8.3%), the significance of which is presently uncertain. The TEL/AML1 chimeric transcript was detected in all patients with t(12;21), whereas the reciprocal AML1/TEL transcript was only found in a subset of patients.…”

Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

“…[11][12][13][14][15][16] In t(12;21)-positive ALL, an extra der(21)t(12;21) has been reported to be more frequently present in relapsed cases. [13][14][15][16] In the present study, we show in a univariate analysis that even in a small number of patients, the presence of this additional abnormality at diagnosis is linked to an unfavorable long-term clinical outcome. Furthermore, we observed that the absence of additional genetic changes in TEL or AML1 is related to a poor prognosis in t(12;21)-positive ALL.…”

“…11,12 Trisomy 21 and duplication of the der(21)t(12;21) are also found in t(12;21)-positive patients, with the latter apparently being more common in relapsed cases. [13][14][15][16] However, the number of patients screened in these studies is limited. The prognostic significance of additional genetic abnormalities in TEL and AML1 is therefore unknown.…”

Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis

“…Some of these events could be reflected on the chromosomal level as nonrandom secondary abnormalities and comprise, in particular, the deletion of the nonrearranged TEL allele, the duplications of the normal chromosome 21 and the der(21)t(12;21) as well as more unspecific ones such as 6q deletions and 9p abnormalities. [21][22][23][24][25][26][27][28][29][30][31][32] Since the t(12;21) is virtually undetectable with conventional cytogenetic procedures, the two preferred screening methods are those with reverse transcriptase polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). 1-6, 9-13,17,21-33 The latter technology has the advantage that it enables the identification and quantification of the most common and, thus, most relevant secondary changes on a single cell level.…”