Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.

Grisolano, Jay L.; Sclar, G M; Ley, Timothy J.

doi:10.1073/pnas.91.19.8989

Cited by 61 publications

(37 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We presume this is due to high expression of a mutant RAR␣ interfering with the RAR͞RXR pathway. To avoid the potential toxicity of the fusion proteins for the developing embryo, we decided to generate transgenic mice in which the APL-specific fusion genes (cDNAs) are under the control of the regulatory elements of the myeloid͞promyelocytic specific cathepsin-G gene (36). To this end, we generated a cathepsin-G minigene expression vector by cloning and modifying a 6.7-kb BamHIBamHI genomic fragment of the hCG gene that is larger than a fragment which has previously been shown to retain promyelocytic specificity in transgenic mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Acute leukemia with promyelocytic features in PML/RARα transgenic mice

Tribioli

Rivi

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

339

263

View full text Add to dashboard Cite

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations involving the retinoic acid receptor ␣ (RAR␣) locus on chromosome 17. In the majority of cases, RAR␣ translocates and fuses with the promyelocytic leukemia (PML) gene located on chromosome 15. The resulting fusion genes encode the two structurally unique PML͞RAR␣ and RAR␣͞PML fusion proteins as well as aberrant PML gene products, the respective pathogenetic roles of which have not been elucidated. We have generated transgenic mice in which the PML͞RAR␣ fusion protein is specifically expressed in the myeloid-promyelocytic lineage. During their first year of life, all the PML͞RAR␣ transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder. Between 12 and 14 months of age, 10% of them develop a form of acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL even in its response to retinoic acid. Our results are conclusive in vivo evidence that PML͞RAR␣ plays a crucial role in the pathogenesis of APL.

show abstract

Section: Resultsmentioning

confidence: 99%

Acute leukemia with promyelocytic features in PML/RARα transgenic mice

Tribioli

Rivi

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

339

263

View full text Add to dashboard Cite

show abstract

“…The APL variant of human AML is characterized by a differentiation block leading to an accumulation of promyelocytes, coagulation abnormalities, chromosomal translocations (Grisolano et al, 1997), PLZF/RARa t(11;17) (He et al, 1998;Cheng et al, 1999), nucleolar phosphoprotein NPM/RARa t(5;17) (Cheng et al, 1999), nuclear mitotic apparatus protein NuMA/RARa t(11;17)(q13;q21) (Sukhai et al, 2004) and Cyclin A1 (Liao et al, 2001) were generated with expression of exogenous cDNA directed exclusively to the myeloid compartment under regulation of human-specific promoter sequences. In particular, the human cathepsin-G (hCG) (Grisolano et al, 1994), MRP8 (Brown et al, 1997) and CD11b (Early et al, 1996) promoters were employed resulting in explicit expression of cDNA in a number of myeloid compartments, and varying disease phenotypes. Transgenic mice with NPM/RARa (Cheng et al, 1999), PML/RARa, PLZF/RARa and NuMa/RARa targeted to the promyelocytic compartment by the hCG vector exhibited diverse inter-and intra-specific phenotypes.…”

Section: Transgenic Modelsmentioning

confidence: 99%

Review: genetic models of acute myeloid leukaemia

2008

View full text Add to dashboard Cite

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.

show abstract

“…[394][395][396] Extensive use of 'classic' transgenics have been engaged in the generation of translocations involving chromosome 17 associated with APML, directed to the myeloid compartment by expression of exogenous cDNA under the regulation of human myeloid-specific sequences. Subsequently, using the human cathepsin-G (hCG) 397 expression vector to direct expression to the promyelocytic compartment, murine models of PML/RARa t(15;17), 398 PLZF/RARa t(11;17), 399,400 NPM/RARa t(5;17), 399 NuMA/RARa t(11;17)(q13;q21) 401 and Cyclin A1 402 were generated. Additionally, the human MRP8 403 expression cassette, expressed in early myeloid progenitors and mature myeloid cells, and CD11b 404 regulatory sequences were used to direct PML/RARa cDNA to myeloid-monocytic and more differentiated granulocytic compartments in further transgenic models.…”

Section: Transgenic Micementioning

confidence: 99%

Animal models of acute myelogenous leukaemia – development, application and future perspectives

2005

View full text Add to dashboard Cite

From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.

show abstract

Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.

Cited by 61 publications

References 23 publications

Acute leukemia with promyelocytic features in PML/RARα transgenic mice

Acute leukemia with promyelocytic features in PML/RARα transgenic mice

Review: genetic models of acute myeloid leukaemia

Animal models of acute myelogenous leukaemia – development, application and future perspectives

Contact Info

Product

Resources

About