Ectopic TAL-1/SCL Expression in Phenotypically Normal or Leukemic Myeloid Precursors: Proliferative and Antiapoptotic Effects Coupled with a Differentiation Blockade

Abstract

The TAL-1 gene specifies a basic helix-loop-helix domain (bHLH) transcription factor, which heterodimerizes with E2A gene family proteins. tal-1 protein is abnormally expressed in the majority of T-cell acute lymphoblastic leukemias (T-ALLs). tal-1 is expressed and plays a significant role in normal erythropoietic differentiation and maturation, while its expression in early myeloid differentiation is abruptly shut off at the level of late progenitors/early differentiated precursors (G. The tal-1 protein, while absent in normal adult T lymphocytes (5), is constitutively expressed in Ͼ60% of T-cell acute lymphoblastic leukemias (T-ALLs), due to the (1;14)(p32;q11) translocation (5,8,18), specific interstitial deletions of the 5Ј noncoding gene region (tal d ) (6), or unidentified alterations (4).LIn the homologous-recombination mouse model, lack of tal-1 determines midgestation embryonic lethality due to the absence of primitive hematopoiesis (44, 48). Furthermore, in vivo and in vitro studies of tal-1 Ϫ/Ϫ embryonic stem cells indicate a crucial role for tal-1 in the generation of all definitive lineages (40,43). In early development tal-1 is also expressed in nervous system, smooth muscle, and endothelial cells (21,29).In adult cells, tal-1 is expressed in normal erythroblasts, megakaryocytes, and mast cells (36, 41), as well as in erythroleukemic, megakaryocytic, and mast cell lines (21, 56). In human hematopoiesis, tal-1 is expressed in hematopoietic progenitor cell (HPC) differentiation/maturation through the erythroid and megakaryocytic lineages (13,36,41,53). Interestingly, tal-1 is also expressed in the early stages of HPC differentiation along the granulopoietic or monopoietic pathways; in both cases, however, the expression is abruptly shut off at the level of late HPC/early differentiated precursors (13). Functional studies with antisense oligodeoxynucleotides targeting tal-1 mRNA indicate a functional role for tal-1 in erythropoiesis, particularly at the advanced HPC differentiation stage, but not in granulo-and monocytopoiesis (13); the functional role in erythropoiesis is further indicated by studies on enforced tal-1 expression in the K562 erythroleukemic line (1,20) and differentiating erythroid HPCs (54a).The tal-1/E2A heterodimer recognizes a subset of E-box responsive elements (27,28). However, tal-1/E2A target genes have not yet been identified. In erythroblasts, formation of the tal-1/E2A complex is inhibited by the HLH Id2 protein, which competes with tal-1 for E2A protein binding (13). Furthermore, tal-1 is associated in complex with Lmo2/rbtn-2 protein in erythroid (54; also, unpublished data) and T leukemic (58) cells.While the function of tal-1 in normal hematopoiesis has been extensively investigated, the effects of aberrant tal-1 expression are under scrutiny (see Discussion). We have investigated the action of ectopic tal-1 on cell proliferation/differentiation and the underlying mechanisms. The selected cell models include phenotypically normal and leukemic myeloid precursors, frozen ...

The CD2-scl transgene alters the phenotype and frequency of T-lymphomas in N-ras transgenic or p53 deficient mice

“…One possible event may be loss of p53. Indeed, similar to our ®ndings, lymphomagenesis was enhanced in the lck-scl mice when crossed with p53 de®cient mice (Condorelli et al, 1996).…”

“…Next, we compared the in vitro survival of thymocytes from p53+/7 mice with or without the scl transgene. In contrast to a previous report examining thymocytes from lck-scl transgenic mice (Condorelli et al, 1996), we found no e ect of scl on in vitro survival of p53+/7 thymocytes (Figure 8a). In addition, scl did not enhance the resistance of p53+/7 thymocytes to ionizing radiation (Figure 8a) or other cell-killing agents such as dexamethasone, ionomycin or anti-Fas antibody (data not shown).…”

“…These data provide further evidence that scl is oncogenic. Recently, two groups have shown that Tcell lymphomas can spontaneously occur in scl transgenic mice when transcription is driven by the lck promoter (Condorelli et al, 1996;Kelliher et al, 1996). However, the latency of tumours in the lck-scl transgenics was at least 6 months and the tumour onset was stochastic, implicating additional genetic events.…”

“…Although there was evidence that scl could function as an oncogene in a v-abl transformed murine cell line , transgenic mice carrying scl coupled to the human T-lymphoid speci®c CD2 enhancer (CD2-scl) did not develop T-cell malignancies despite high levels of scl expression in their thymocytes (Robb et al, 1995b;Larson et al, 1996). Recently, a role for scl in leukemogenesis was con®rmed by two groups who showed that animals carrying an scl transgene driven by the proximal lck promoter develop thymic T-cell lymphomas (Condorelli et al, 1996;Kelliher et al, 1996). The discrepancies of these results may be due to di erent timing of expression.…”

p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice

“…We and others have shown that misexpression of Tal1 in the thymus alters thymocyte development by interfering with the expression of E47/HEB target genes including Rag1/2, Pre-Ta, CD4, CD5, CD3 and the TCRabchains (Herblot et al, 2000;O'Neil et al, 2001O'Neil et al, , 2004. Although Tal1 induces leukemia in mice, it does so after a long latency revealing that additional genetic events are required (Condorelli et al, 1996;Kelliher et al, 1996). Analysis of the INK4A/ARF locus in human T-ALL patients has revealed frequent homozygous deletion of exon 2, the exon common to both p16 INK4A and p14 ARF genes (Hebert et al, 1994;Cayuela et al, 1995Cayuela et al, , 1996Drexler, 1998;Gardie et al, 1998;Ferrando et al, 2002).…”