Defining the oncogenic function of the TEL/AML1 (ETV6/RUNX1) fusion protein in a mouse model

Abstract

The t(12;21) translocation, generating the TEL/AML1 fusion protein, is the most common genetic lesion in childhood cancer. Using a bone marrow transplantation model, we demonstrate that TEL/AML1 expression impinges on normal hematopoietic differentiation, leading to the in vivo accumulation and persistence of an early progenitor compartment with a Sca1 þ /Kit hi /CD11b þ phenotype and an increased self-renewal capacity, as documented by replating assays in vitro. Differentiation of these cells is not blocked, but the frequency of mature blood cells arising from TEL/AML1-transduced progenitors is low. Impaired differentiation is prominently observed in the pro-B-cell compartment, resulting in an proportional increase in early progenitors in vivo, consistent with the t(12;21) ALL phenotype. Despite the accumulation of both multipotent and B-cell progenitors in vivo, no leukemia induction was observed during an observation period of over 1 year. These results are consistent with findings in twins with concordant ALL, showing that TEL/AML1 generates a preleukemic clone in utero that persists for several years in a clinically covert fashion. Furthermore, our studies showed that the pointed domain of TEL/AML1, which recruits transcriptional repressors and directs oligomerization with either TEL/ AML1 or wild-type TEL, was essential for the observed differentiation impairment and could not be replaced with another oligomerization domain.

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

“…Thus, we demonstrated that TEL-AML1 enhanced the self-renewal capacity of B-cell progenitors in colony-forming assays in vitro and conferred a competitive advantage on hematopoietic reconstitution in vivo (Morrow et al, 2004). Other studies observed an accumulation of early B-cell progenitors expressing TEL-AML1 (Tsuzuki et al, 2004;Fischer et al, 2005). To understand further the mechanism of TEL-AML1 action, we have analysed the activity of TEL-AML1 deletion mutants in vitro and in vivo.…”

Combined high-resolution array-based comparative genomic hybridization and expression profiling of ETV6/RUNX1-positive acute lymphoblastic leukemias reveal a high incidence of cryptic Xq duplications and identify several putative target genes within the commonly gained region

“…7,8 Several lines of evidence suggest that ETV6/RUNX1 is not sufficient for leukemic transformation, such as detection of the gene fusion in Guthrie cards from patients who later developed ETV6/RUNX1-positive ALLs, 9 identical gene fusions in twins with concordant leukemia, 10 identification of the chimeric transcript in normal cord blood samples 11 and lack of leukemia in mouse models. 12 Thus, although t(12;21)-positive preleukemic clones, at least in some cases, arise already in utero, additional mutations are most likely required for overt leukemia.…”

Genome‐wide analysis of cytogenetic aberrations in ETV6/RUNX1‐positive childhood acute lymphoblastic leukaemia

“…This initiating event, seen as early as in utero (Wiemels et al, 1999;Hjalgrim et al, 2002), most likely requires additional genetic changes in order to lead to leukaemia e.g. ETV6/RUNX1 transcripts have been demonstrated in normal cord blood samples at low levels (Mori et al, 2002;Lausten-Thomsen et al, 2011) and neither ETV6/ RUNX1-positive knock-in mouse models nor carriers of ETV6/RUNX1-positive pre-leukaemic cells will all develop leukaemia (Fischer et al, 2005;Hong et al, 2008). Thus, the development of ETV6/RUNX1-positive leukaemia requires one or more secondary genetic changes and previous studies have indeed shown additional genetic changes in the majority of ETV6/RUNX1-positive childhood ALL patients (Forestier et al, 2007;Mullighan et al, 2007;Kawamata et al, 2008;Lilljebjorn et al, 2007Lilljebjorn et al, , 2010Parker et al, 2008;Mullighan et al, 2008;van Delft et al, 2011).…”