Biology, Natural History and Clinical Features of TEL/AML 1-Positive Childhood Leukaemias (pp. 163-184)
Authors: Zuna, Jan (Medical School Charles University Prague, Czech Republic)
Abstract: The TEL/AML1 (ETV6/RUNX1) fusion gene is derived from the t(12;21)(p13;q22) translocation and became recently one of the crucial genetic changes in paediatric haematology. The t(12;21) is the most frequent chromosomal aberration in childhood acute lymphoblastic leukaemia (ALL) being present in approximately 20-25% of all newly diagnosed children. AML1 gene is a part of CBF transcription factor that plays essential role in haematopoiesis. TEL/AML1 acts presumably as a dominant inhibitor of the nontranslocated AML1 allele and blocks transcription of CBF-dependent genes. Besides the t(12;21) TEL and AML1 genes are involved in a high number of different aberrations in haematological malignancies. TEL is often fused to genes encoding thyrosin-kinases; AML1 is altered also in a substantial number of acute myeloid leukaemias (most frequently as AML1/ETO fusion). Patients with the TEL/AML1 fusion form relatively homogenous group of ALL. These children are diagnosed mostly in the pre-school age with B cell precursor immunophenotype of leukaemic blasts and they have favourable treatment outcome. Studies on identical twins and triplets with concordant ALL and retrospective scrutiny of neonatal blood spots have provided evidence that TEL/AML1 fusion often arises pre-natally, possibly as the first or initiating event. The "pre-leukaemic" clone with TEL/AML1 can persist postnatally for extended periods and another post-natal genetic event is required for overt leukaemia. It has been suggested that some late relapses of TEL/AML1-positive ALL might be in fact "new leukaemias" arising from the same "pre-leukaemic" TEL/AML1-positive clone but triggered by a new post-natal hit – possibly by deletion of the non-translocated TEL allele.