Outcome and lineage involvement in t(12;21) childhood acute lymphoblastic leukaemia

Abstract

Summary. The t(12;21)(p13;q22) translocation has been described recently as the most recurrent genetic lesion in paediatric acute lymphoblastic leukaemias (ALLs). It has also been associated with B-precursor lineage involvement and good outcome.We tested 51 diagnostic paediatric ALLs and found 11 cases with molecular evidence of the t(12;21). Interestingly, amongst t(12;21) positive patients, we report three cases with hybrid phenotype, and two cases showing an aggressive and fatal disease. Our data show that the t(12;21) does not represent an independent good-risk indicator. Long followups and additional molecular investigations are needed to assess the prognostic and pathogenetic relevance of t(12;21) in childhood ALLs.Keywords: TEL, AML1, childhood ALL, translocations, prognosis.The t(12;21)(p13;q22) translocation has been described recently as the most frequent genetic lesion of childhood ALLs. Although almost undetectable at the cytogenetic level, it has been reported to occur in 16-36% of childhood ALL series when tested by molecular techniques (Romana et al, 1995b;Shurtleff et al, 1995). The t(12;21), by fusing the TEL gene on chromosome 12p (Golub et al, 1994) to the AML1 gene on chromosome 21q , produces two hybrid transcripts, TEL/AML1 and AML1/TEL, the former being more consistently expressed in rearranged cases. This translocation has been associated with B-precursor lineage involvement and it has been suggested that the TEL/AML1 transcript expression, though playing a leukaemogenic role, may identify a subset of ALL patients with excellent prognosis (Romana et al, 1995b;Shurtleff et al, 1995).In order to assess the frequency and investigate the prognostic value of this translocation in our paediatric population, we tested 51 cases of childhood ALL for the presence of the TEL/AML1 hybrid transcript.We found that the t(12;21) associates with more heterogenous findings than previously reported, with regard to both lineage involvement and outcome. PATIENTS AND METHODSPatients. 51 consecutive cases of childhood ALL at presentation, age 2-15 years, diagnosed between 1992 and 1996, were included in the present study. B-mature ALLs were excluded. Patients were enrolled in the Associazione Italiana di Ematologia Oncologia Pediatrica (AIEOP) Italian protocols for ALLs, according to the risk factors at diagnosis.RT-PCR analysis. Briefly, total RNA was extracted from bone marrow (BM) samples by the guanidinium/thiocyanate-phenol/chloroform method. 1 mg of RNA was reverse transcribed into cDNA by incubation at 42ЊC for 45 min with 50 U Moloney murine leukaemia virus reverse transcriptase (RT) and random examer primers (Perkin-Elmer, Norwalk, Ct., U.S.A.) followed by RT denaturation at 99ЊC for 5 min. For PCR amplification we used the conditions and oligonucleotide primers described by Romana et al (1995b). Adopting the previous PCR conditions, and adding the TEL sense 5 0 oligonucleotide (5'-CGTGGATTTCAAACAGTCCA-3 0 ) and 3 0 TEL antisense oligonucleotide (TEL antisense: 5 0 -GGCTCTGGACATTTTCTCAT-3 0 ), the expr...

Immunophenotyping of Acute Leukaemias. Immunophänotypisierung akuter Leukämien

“…The high frequency of myeloid antigen expression (i.e. CD 13 ^nd/or CD33) that was reported originally in a large series of children with ETV6-AML1 rearrangement enrolled in the German and Italian miilticentre trials was confirmed by other reports [177][178][179]. It is interesting to note that other characteristic immunophenotypic features have been described recently that are highly predictive of ETV6-AML1 rearrangement and may be implemented as a screening test for this genetic 'abnormality [296].…”

Correspondence

“…& Alexander, G.J.M. (1997) We read with interest the recent report by Lanza et al (1997) relating to the poor outcome of two of their 11 TEL/AML1positive patients. Here we describe a child with relapsed acute lymphoblastic leukaemia (ALL), TEL/AML1 transcript and p16 homozygous deletion.…”

“…Rearrangement of the TEL and AML1 genes has been associated with excellent prognosis (Shurtleff et al, 1995). Nevertheless, recently some TEL/AML1-positive patients with an extremely adverse prognosis have been detected (Lanza et al, 1997). This could be related to the presence of additional molecular lesions.…”

“…The TEL/AML1 fusion has been described in the B-precursor lineage ALL. Some cases have been published with a hybrid immunophenotype (Cayuela et al, 1996;Lanza et al, 1997), and the case described here corresponds to another The same filter dehybridized and rehybridized with the p16 probe. The case described (lane 3) shows very weak hybridizing bands compared with bands detected after probing with B859.…”

Minimal residual disease studies are beneficial in the follow‐up of TEL/AML1 patients with B‐precursor acute lymphoblastic leukaemia

“…Initially, it was suggested that therapy in this group of patients was so successful that relapse never occurred (Shurtleff et al, 1995;Cayuela et al, 1996;McLean et al, 1996). Nevertheless, more recent studies have shown that relapses do occur Harbott et al, 1997;Lanza et al, 1997;Loh et al, 1998).…”