Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene

Dobson, Claire; Warren, Alan J.; Pannell, Richard; Förster, A.; Rabbitts, Terence H.

doi:10.1093/emboj/19.5.843

Cited by 129 publications

(122 citation statements)

References 38 publications

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“…Conversely, Mll AT-hooks-lacZ fusion failed to develop acute leukemias in an experimental period of 12 months. 64,65 In our experiments, complete myelomonocytic differentiation and cell death obtained with MLL-AF9 forced expression was not seen with expression of the amino terminal AT-hook motifs alone, but required downstream MLL sequences, including the MT domain. The MT domain, like the AT-hook motifs, has been previously defined as necessary for leukemic transformation.…”

Section: Leukemiamentioning

confidence: 52%

The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

et al. 2000

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The mixed-lineage leukemia gene (MLL) is associated with more than 25 chromosomal translocations involving band 11q23 in diverse subtypes of human acute leukemia. Conditional expression of a 50 kDa amino terminal fragment spanning the AT hook motifs of MLL (MLL3AT) causes cell cycle arrest, upregulation of p21 Cip1 and p27 Kip1 and partial monocytic differentiation of the monoblastic U937 cell line, suggesting a major role for MLL3AT in MLL-AF9-induced myelomonocytic differentiation. In this study, we analyzed the subcellular localization of conditionally expressed MLL3AT in both U937 and HeLa cell lines. Immunofluorescence staining, confocal laser scanning microscopy and immunoelectron microscopy indicated that MLL3AT, like endogenous MLL, localized in the nucleoplasm in a punctate pattern of distribution, including regions attached to the nuclear envelope and the periphery of the nucleolus. We found that MLL3AT and endogenous MLL were present in interphase nuclear matrices and colocalized with topoisomerase II to mitotic chromosomal scaffolds. Nucleoplasm and nucleolar localization was observed even for MLL-AF9 and MLL-AF4 conditionally expressed chimeric proteins, suggesting a common target conferred by the amino terminus of MLL to many if not all the chimeric MLL proteins. The nuclear matrix/scaffold association suggests a role for the amino terminus of MLL in the modulation of chromatin structure, leading to epigenetic effects on the maintenance of gene expression.

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Section: Leukemiamentioning

confidence: 52%

The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

et al. 2000

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“…As mentioned in the techniques section, in this approach the mutated exogenous cDNA is targeted in-frame directly to a pre-defined locus by homologous recombination in the ES cells and employed in developing knock-in models of the following: AML1-ETO t(8;21) (Yergeau et al, 1997;Okuda et al, 1998;Fenske et al, 2004), PLZF-RARa t(11;17) (He et al, 1999), CBFb-MYH11 inv(16) t(16;16) found in AML subtype FAB M4Eo (that is myelomonocytic differentiation together with increased eosinophilic progenitors) (Castilla et al, 1996), CBFb-GFP (Kundu et al, 2002), MLL-AF9 t(9;11) found in AML FAB M5 (that is myelomonocytic variants) (Dobson et al, 1999) and MLL-lacZ (Dobson et al, 2000). Resultant AML-ETO or CBFb-MYH11 knock-in fusion genes resulted in embryonic lethality owing to lack of definitive embryonic haematopoiesis in a manner remarkably similar to that of the corresponding (AML1 À/À , CBFb À/À ) knockout animals.…”

Section: Knock-in Modelsmentioning

confidence: 99%

Review: genetic models of acute myeloid leukaemia

2008

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The use of genetically engineered mice (GEM) have been critical in understanding disease states such as cancer, and none more so than acute myelogenous leukaemia (AML), a disease characterized by over 100 distinct chromosomal translocations. A substantial proportion of cases exhibiting recurrent reciprocal translocations at diagnosis, such as t(8;21) or t(15;17) have been exhaustively studied and are currently employed in clinical diagnosis. However, a definitive conclusion regarding the leukaemogenic potential of defined transgenes for this disease remains elusive. While it is increasingly apparent that a number of cooperating mutations are necessary to develop a leukaemic phenotype, the number of models reflecting these synergisms remains few. Furthermore, little emphasis has been paid to the effect of chromosomal translocations other than recurrent genetic abnormalities, with no models reflecting the multiple abnormalities observed in high-risk cases of AML accounting for 8-10% of adult AML. Here we review the differing technologies employed in generation of GEM of AML. We discuss the relevance of GEM AML from embryonic stem cell-mediated (for example retinoic acid receptor-a fusions and AML1/ETO) models; through to the valuable retroviral-mediated gene transfer models. The latter have been used to great effect in defining the transforming properties of chromosomal translocation products such as MLL (found in 5-6% of all AML cases) and NUP98 (denoting poor prognosis in therapy-related disease) and particularly when co-transduced with bad prognostic factors such as Flt3 mutations. Finally, we comment on the emergence of newer transduction technologies, which can regulate the level of expression to defined cell lineages in both primary murine and human xenografts, and discuss how combining multiple genetic modalities, more relevant models of this complex disease are being generated.

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“…The first is transcriptional activation properties conferred by fusion partners (e.g. AF10, AFX, CBP, ENL, ELL) (Rubnitz et al, 1994;Slany et al, 1998;DiMartino et al, 2000DiMartino et al, , 2002Lavau et al, 2000) or the second is dimerization properties conferred on the fusion molecule that are an important component of tumourigenicity (Dobson et al, 2000;Martin et al, 2003;So et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology

et al. 2006

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MLL-AF4 fusion is the most common consequence of chromosomal translocations in infant leukaemia and is associated with a poor prognosis. MLL-AF4 is thought to be required in haematopoietic stem cells to elicit leukaemia and may be involved in tumour phenotype specification as it is only found in B-cell tumours in humans. We have employed the invertor conditional technology to create a model of MLL-AF4, in which a floxed AF4 cDNA was knocked into Mll in the opposite orientation for transcription. Cell-specific Cre expression was used to generate Mll-AF4 expression. The mice develop exclusively B-cell lineage neoplasias, whether the Cre gene was controlled by B-or T-cell promoters, but of a more mature phenotype than normally observed in childhood leukaemia. These findings show that the MLL-AF4 fusion protein does not have a mandatory role in multi-potent haematopoietic stem cells to cause cancer and indicates that MLL-AF4 has an instructive function in the phenotype of the tumour.

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Tumorigenesis in mice with a fusion of the leukaemia oncogene Mll and the bacterial lacZ gene

Cited by 129 publications

References 38 publications

The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

The amino terminus targets the mixed lineage leukemia (MLL) protein to the nucleolus, nuclear matrix and mitotic chromosomal scaffolds

Review: genetic models of acute myeloid leukaemia

A conditional model of MLL-AF4 B-cell tumourigenesis using invertor technology

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