Hematopoietic Stem Cell Expansion and Distinct Myeloid Developmental Abnormalities in a Murine Model of the <i>AML1</i>-<i>ETO</i> Translocation

Guzman, Cristina G. de; Warren, Alan J.; Zhang, Zheng; Gartland, Larry; Erickson, Paul F.; Drabkin, Harry A.; Hiebert, Scott W.; Klug, Christopher A.

doi:10.1128/mcb.22.15.5506-5517.2002

Cited by 158 publications

(154 citation statements)

References 46 publications

(47 reference statements)

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“…Assays of AML1-ETO function employing either transduction of primary hematopoietic progenitors or inducible transgenic mice have confirmed its role in early multipotent progenitor expansion [4,[23][24][25][26]. This role is more subtle than the differentiation blockade observed in transfected cell lines and argues against a simple unimodal model of transcriptional repression of RUNX1 target genes.…”

Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 91%

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability.

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Section: Challenges To the Classical Model: Gene Expression Profilesmentioning

confidence: 91%

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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“…As bone marrow cells and PBLs are readily available for in vitro exploitation, significant efforts have focussed on transfer of AML disease genes into both murine and human haematopoietic cells (Table 3) AML/ETO t(8;21) Retroviral transfection and transduction of AML/ETO (de Guzman et al, 2002) into an enriched HSC population resulted chimeric mice with haematopoietic abnormalities, including a significant increase in immature eosinophil myelocytes, as observed in patients with t(8;21). Conversely, mice transplanted with cells expressing only the DNA-binding domain of AML1 (de Guzman et al, 2003) exhibited normal haematopoiesis, demonstrating that the ETO-binding domain is requisite in development of AML/ETO-associated haematopoietic anomalies.…”

Section: Chimeric 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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“…[11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia.…”

mentioning

confidence: 99%

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

Peterson

Yan

et al. 2012

Blood

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IntroductionAcute myeloid leukemia (AML) is a common hematologic malignancy characterized by an abnormal accumulation of myeloid precursors in the bone marrow and blood. Similar to many other types of cancer, genetic abnormalities are associated with the development of AML, particularly chromosomal translocations that result in novel fusion proteins. One of the common translocations implicated in AML is the 8q22;21q22 translocation [t(8;21)]. 1 Based on the French-American-British (FAB) classification of leukemic cells, t(8;21) is associated with nearly 40% of the AML cases with the FAB M2 phenotype. 2 t(8,21) involves the AML1 (RUNX1) gene on chromosome 21 and the ETO (MTG8, RUNX1T1) gene on chromosome 8. [3][4][5] AML1 is the DNA-binding subunit of the core binding factor (CBF) transcription factor complex. Its N-terminus contains a highly conserved DNA binding domain called the runt homology domain (RHD). t(8;21) fuses the N-terminus of AML1 including RHD in-frame with almost the entire ETO protein to form AML1-ETO. [3][4][5][6] This fusion protein acts as a dominant negative form of AML1 during embryogenesis. 7,8 It functions as a transcriptional repressor by interacting with NCoR/SMRT/HDAC. 9,10 AML1-ETO was shown to activate expression of BCL-2 and p21, possibly via interacting with p300. [11][12][13] AML1-ETO promotes stem cell renewal and blocks hematopoietic differentiation. [14][15][16] However, its role in blocking cell-cycle progression and promoting apoptosis contradicts its function in promoting leukemogenesis and therefore requires secondary mutagenic events for full transformation. 17,18 We previously identified a single nucleotide insertion that resulted in a truncated AML1-ETO protein (AML1-ETOtr or AEtr), which rapidly promoted leukemia. 19 Subsequently, we identified a C-terminally truncated variant of AML1-ETO named AML1-ETO9a (AE9a), resulting from alternative splicing and found to coexist with full-length AML1-ETO in most analyzed t(8;21) AML patients. 20 Similar to AEtr, AE9a causes a rapid onset of leukemia in mice, 20 which provides a useful mouse model to study the molecular biology of t(8;21) leukemia.To understand the molecular mechanism of AML1-ETOrelated leukemia development and to explore novel therapeutic targets to treat this type of leukemia, in this study we combined gene expression microarray and promoter occupancy (ChIP-chip) analyses to identify genes directly modulated by AE9a in primary murine leukemia cells. Among the common targets of microarray and ChIP-chip assays, approximately 30% show human t(8;21)-specific up or down-regulation compared with AML that have other chromosomal abnormalities. CD45, a protein tyrosine phosphatase and a negative regulator of cytokine/growth factor receptor and JAK/STAT signaling, 21-23 is among those targets. Its expression is down-regulated in AE9a leukemia cells. Consequently, JAK/STAT signaling is enhanced in these leukemia cells. We show that re-expression of CD45 suppresses JAK/STAT activation, delays leukemia development by AE9a an...

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Hematopoietic Stem Cell Expansion and Distinct Myeloid Developmental Abnormalities in a Murine Model of the AML1-ETO Translocation

Cited by 158 publications

References 46 publications

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Review: genetic models of acute myeloid leukaemia

Combined gene expression and DNA occupancy profiling identifies potential therapeutic targets of t(8;21) AML

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