The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice

O’Neil, Jennifer; Billa, Marilisa; Oikemus, Sarah; Kelliher, Michelle A.

doi:10.1038/sj.onc.1204519

Cited by 57 publications

(63 citation statements)

References 51 publications

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“…The increased cell cycle activity in the preleukemic tal1 thymus results in apoptosis that is ink4a/arf-dependent, suggesting that Tal1 triggers the p19Arf-p53 apoptotic pathway. However, mice expressing a DNA-binding mutant of Tal1 develop disease, which questions the overall biological significance of the effects of Tal1 on the cell cycle (O'Neil et al, 2001). We speculate that the inappropriate cell cycle entry and apoptosis associated with Tal1 expression in vivo may provide an additional selective pressure to disrupt the ink4a/arf locus.…”

Section: Discussionmentioning

confidence: 96%

“…Mice and tumor cell culture Proximal lck-tal1 mice and mut tal1 R188G;R189G have been described previously (Kelliher et al, 1996;O'Neil et al, 2001). Ink4a/arf null, p16 ink4a À/À and p19 arf À/À mice have been described previously (Serrano et al, 1996;Kamijo et al, 1997;Sharpless et al, 2001) and were obtained from the Mouse Models of Human Cancers Consortium (MMHCC).…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 94%

“…DNA-binding mutant of Tal1 (Tal1R188G;R189G) inhibit E2A transcriptional activity and induce leukemia in mice (O'Neil et al, 2001(O'Neil et al, , 2004. Thus, the S phase induction may be mediated by the ability of Tal1 (and the DNA-binding mutant of Tal1) to inhibit the transcriptional activity of E47/HEB.…”

Section: S Phase Induction Is Dependent On a Functional Dna-binding Dmentioning

confidence: 99%

“…Interestingly, mice expressing a DNA-binding mutant of Tal1 exhibit blocks in thymocyte development (O'Neil et al, 2001), but do not show any changes in cell cycle. Hence, the ability to stimulate thymocyte proliferation appears dependent on the ability of Tal1 to bind DNA, and also appears to be independent of the effects of Tal1 on thymocyte differentiation.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Analysis of the INK4A/ARF locus in human T-ALL patients revealed frequent deletions in exon 2, the exon common to both p16 INK4A and p14 ARF . Other studies have described selective deletion of exon 1b of p14 ARF or methylation of the p16 INK4A promoter. Therefore, it is unclear from these studies whether loss of p16 INK4A and/or p14 ARF contributes to the development of T-ALL. To elucidate the relative contribution of the ink4a/arf locus to T-cell leukemogenesis, we mated our tal1 transgenic mice to ink4a/arfÀ/À, p16 ink4a À/À, and p19 arf À/À mice and generated tal1/ink4a/arf þ /À, tal1/p16 ink4a þ /À, and tal1/p19 arf þ /À mice. Each of these mice developed T-cell leukemia rapidly, indicating that loss of either p16 ink4a or p19 arf cooperates with Tal1 to induce leukemia in mice. Preleukemic studies reveal that Tal1 expression stimulates entry into the cell cycle and thymocyte apoptosis in vivo. Interestingly, mice expressing a DNA-binding mutant of Tal1 do not exhibit increases in S phase cells. The S phase induction is accompanied by an increase in thymocyte apoptosis in tal1 transgenic mice. Whereas apoptosis is reduced to wild-type levels in tal1/ink4a/ arfÀ/À mice, S phase induction remains unaffected. Thus, Tal1 stimulates cell cycle entry independent of the ink4a/arf locus, but its ability to induce apoptosis is Ink4a/Arfdependent.

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: S Phase Induction Is Dependent On a Functional Dna-binding Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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Lymphoid Malignancies

Teitell

Pandolfi

2004

Mouse Models of Human Cancer

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Malignant transformation may occur at any point during lymphoid cell maturation, resulting in stage‐ and lineage‐specific cancers of the immune system. Many in‐bred and engineered mouse strains develop specific lymphoid cancers, providing potentially useful models of human malignancy with insight for pathogenetic mechanisms. Newer techniques, targeting dysregulated gene expression to specific developmental stages portend newer, more accurate mouse models in the future. These models will likely have an increasing role in evaluating targeted therapeutic strategies for efficacy.

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Assembly of the oncogenic DNA‐binding complex LMO2‐Ldb1‐TAL1‐E12

et al. 2007

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The nuclear proteins TAL1 (T-cell acute leukaemia protein 1) and LMO2 (LIM-only protein 2) have critical roles in haematopoietic development, but are also often aberrantly activated in T-cell acute lymphoblastic leukaemia. TAL1 and LMO2 operate within multifactorial protein-DNA complexes that regulate gene expression in the developing blood cell. TAL1 is a tissue-specific basic helix-loop-helix (bHLH) protein that binds bHLH domains of ubiquitous E-proteins, (E12 and E47), to bind E-box (CANNTG) DNA motifs. TAL1(bHLH) also interacts specifically with the LIM domains of LMO2, which in turn bind Ldb1 (LIM-domain binding protein 1). Here we used biophysical methods to characterize the assembly of a five-component complex containing TAL1, LMO2, Ldb1, E12, and DNA. The bHLH domains of TAL1 and E12 alone primarily formed helical homodimers, but together preferentially formed heterodimers, to which LMO2 bound with high affinity (K(A) approximately 10(8) M(-1)). The resulting TAL1/E12/LMO2 complex formed in the presence or absence of DNA, but the different complexes preferentially bound different Ebox-sequences. Our data provide biophysical evidence for a mechanism, by which LMO2 and TAL1 both regulate transcription in normal blood cell development, and synergistically disrupt E2A function in T-cells to promote the onset of leukaemia.

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The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice

Cited by 57 publications

References 51 publications

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

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

Lymphoid Malignancies

Assembly of the oncogenic DNA‐binding complex LMO2‐Ldb1‐TAL1‐E12

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