The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion

Abstract

Analysis of a growing number of chromosomal translocations in human tumors have shown that they frequently result in gene fusions encoding chimeric proteins. We have characterized the recurrent t(12;21)(p12;q22) translocation present in human B-lineage acute leukemias. This translocation fused two genes, tel and AML1, that have previously been described in chromosomal translocations specific for myeloid malignancies. These two genes therefore belong to an increasing number of human genes that are involved in a variety of hematopoietic malignant disorders and can be rearranged with numerous partners. Interestingly, in these acute leukemias, deletion of the other tel allele from the normal chromosome 12 was associated with the tel rearrangement, whereas both tel alleles were present in the chronic leukemias bearing a t(5;12) that we have tested.

Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA

“…Therefore the good outcome overall for abn12p patients in this trial suggests that it is the involvement of a gene or genes on 12p, rather than dic(9;12) per se which renders these cases particularly responsive to treatment (Mahmoud et al, 1992;Behrendt et al, 1995). A likely candidate gene in these cases is TEL (Romana et al, 1995). This subgroup and two others, abn11q (including t(4;11) cases) and hypodiploid, added prognostic significance to all other variables combined.…”

The Aml1‐eto Chimaeric Transcription Factor in Acute Myeloid Leukaemia: Biology and Clinical Significance

“…As mentioned earlier, the genes encoding the AML1/CBFb complex are the most frequent targets of chromosomal rearrangements in human leukaemia. The AML1 gene is rearranged by t(3;21)[AML1-EVI1] in myelodysplasia and blast transformation of chronic myeloid leukaemia (Nucifora et al, 1993a, c;Mitani et al, 1994), and by t(12;21)[TEL-AML1] in paediatric acute lymphoblastic leukaemia (ALL) (Golub et al, 1995;Romana et al, 1995), whereas CBFb is targeted by inv(16) and t(16;16) in AML-M4Eo (Liu et al, 1993). Although these leukaemias represent a range of immunologic and morphologic phenotypes, the recurrent involvement of the AML1/CBFb complex suggests a common underlying pathogenesis.…”

“…Similarly, the Drosophila protein Lozenge, which is related to Runt, is essential for the normal patterning of cells in the eye (Daga et al, 1996). In addition, the mammalian AML3 protein has been shown to function as a master regulator essential for osteoblast differentiation (Ducy et al, 1997;Komori et al, 1997;Otto et al, 1997;Mundlos et al, 1997;Rodan & Harada, 1997). Inactivation of AML3 in mice results in the absence of bone ossi®cation (Komori et al, 1997;Otto et al, 1997;Mundlos et al, 1997), whereas inactivating mutations in man result in cleidocranial dysplasia Mundlos et al, 1997).…”

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

“…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).…”

“…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 probes for ETV6 (Fig 1).…”