AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency

Schwieger, Maike; Löhler, Jürgen; Friel, Jutta; Scheller, Marina; Horak, Ivan D.; Stocking, Carol

doi:10.1084/jem.20020824

Cited by 137 publications

(163 citation statements)

References 79 publications

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“…Subsequently, AML/ETO t(8;21) was transduced to bone marrow derived from mice deficient of the interferon regulatory factor ICSBP (Schwieger et al, 2002), implicated as a suppressor of myeloid neoplasia (Holtschke et al, 1996;Gabriele et al, 1999;Scheller et al, 1999) and was found to synergize with ICSBP deficiency to incite myeloblastic conditions evocative of AML. Furthermore, activating mutations in receptor tyrosine kinases, for example TEL/PDGFbR and Flt3, were found to cooperate with AML/ETO (Grisolano et al, 2003), NUP98/HOXA9 t(7;11) (Dash et al, 2002) and PML/RARa t(15;17) (Kelly et al, 2002) causing AML (FAB M2)-type leukaemia, AML and APL, respectively in transduced mice.…”

Section: Cdx2mentioning

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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Section: Cdx2mentioning

confidence: 99%

Review: genetic models of acute myeloid leukaemia

2008

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“…Analyses of various mouse models of AML1-ETO expression also demonstrate that AML1-ETO plays a critical role in leukemogenesis. By itself however, it is not sufficient for disease development [45][46][47][48][49]. Since AML1-ETO has the AML1 DNA binding domain and binds to the same DNA sequence as AML1, it has been believed that the function of AML1-ETO is through the regulation of gene expression.…”

Section: Discussionmentioning

confidence: 99%

Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO

Hines¹,

Boyapati²,

Zhang³

2007

Blood Cells, Molecules, and Diseases

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The AML1-ETO fusion protein is generated from the 8;21 chromosome translocation that is commonly identified in acute myeloid leukemia. AML1-ETO is a DNA binding transcription factor and has been demonstrated to play a critical role in promoting leukemogenesis. Therefore, it is important to define the molecular mechanism of AML1-ETO in the regulation of gene expression. Here, we report that the effect of AML1-ETO on the promoter of multidrug resistance-1 (MDR1) gene, a known AML1-ETO target, is highly cell type specific. Besides observing repression of the MDR1 promoter in C33A and CV-1 cells as reported previously, AML1-ETO strongly activated the promoter in K562 and B210 cells. More importantly, this activation required both the AML1 and ETO portions of the fusion protein, but did not depend on the AML1 binding site in MDR1 promoter. Furthermore, results from promoter deletion analysis and chromatin immunoprecipitation assays suggested that this activation effect was likely through the influence of the general transcription machinery rather than promoter-specific factors. Based on these data, we propose that AML1-ETO may have opposing effects on gene expression depending on the various conditions of the cellular environment.

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“…147 In all three hematopoietic cell types, IRF8 expression decreased with aging. Previously, IRF8 insufficiency has been associated with the development of hematopoietic malignancies in murine models, 148,149 and many human hematopoietic malignancies (AML, CML, MDS) display decreased IRF8 expression. [150][151][152] These results suggest that IRF8 insufficiency with aging may facilitate transformation, but additional studies will be required to confirm these results and to identify potential other T-ARECs, if they exist.…”

Section: Effects Of Aging On Hematopoietic Expressionmentioning

confidence: 99%

Gene expression changes in normal haematopoietic cells

Lionberger¹,

Stirewalt²

2009

Best Practice & Research Clinical Haematology

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The complexity of the healthy hematopoietic system is immense, and as such, one must understand the biology driving normal hematopoietic expression profiles when designing experiments and interpreting expression data that involves normal cells. This chapter seeks to present an organized approach to the use and interpretation of gene profiling in normal hematopoiesis and broadly illustrates the challenges of selecting appropriate controls for high-throughput expression studies.

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AML1-ETO Inhibits Maturation of Multiple Lymphohematopoietic Lineages and Induces Myeloblast Transformation in Synergy with ICSBP Deficiency

Cited by 137 publications

References 79 publications

Review: genetic models of acute myeloid leukaemia

Review: genetic models of acute myeloid leukaemia

Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO

Gene expression changes in normal haematopoietic cells

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