Review: genetic models of acute myeloid leukaemia

McCormack, Emmet; Bruserud, Øystein; Gjertsen, Bjørn Tore

doi:10.1038/onc.2008.16

Cited by 46 publications

(43 citation statements)

References 111 publications

(107 reference statements)

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“…Numerous tumor models are available but drawbacks are associated with each. For example, subcutaneously implanted tumor models 53 do not realistically reflect disseminated disease whereas genetically engineered mice to model AML driven by gene mutations 54 are not useful in the evaluation of lintuzumab since murine and human CD33 proteins differ in both expression profile and biology. 55 Mouse xenografts generated with primary human AML leukemic stem cells 56,57 may better simulate the human disease, but there are problems in obtaining sufficient numbers of leukemic patient stem cells and in the variability in engraftment of these cells in mice.…”

Section: Discussionmentioning

confidence: 99%

Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Sutherland

Lewis

et al. 2009

mAbs

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Section: Discussionmentioning

confidence: 99%

Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Sutherland

Lewis

et al. 2009

mAbs

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“…acute myeloid leukemia ͉ genetic model ͉ runx A cute myeloid leukemia (AML) is characterized by the clonal growth of immature blood cells and is often associated with non-random chromosomal translocations that impair the function of key hematopoietic regulators (1). For instance, the t(8:21)(q22;q22) translocation, which is present in 10 to 15% of all cases of AML, affects the transcription factor AML1 (2).…”

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confidence: 99%

A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO

Osman

Gobert

Ponthan

et al. 2009

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

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The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ ؉ progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.acute myeloid leukemia ͉ genetic model ͉ runx A cute myeloid leukemia (AML) is characterized by the clonal growth of immature blood cells and is often associated with non-random chromosomal translocations that impair the function of key hematopoietic regulators (1). For instance, the t(8:21)(q22;q22) translocation, which is present in 10 to 15% of all cases of AML, affects the transcription factor AML1 (2). AML1 is required at multiple steps of hematopoiesis from the emergence of definitive hematopoietic stem cells to the differentiation of myeloid and lymphoid lineages (3). AML1 is a member of the RUNX family of transcription factors that are characterized by a highly conserved DNA binding domain. AML1-ETO, the product of the t(8;21) translocation, contains AML1 N-terminal portion, including its DNA binding domain, fused to the almost entire transcriptional corepressor ETO (4, 5). While it was proposed initially that AML1-ETO promotes leukemia at least in part by repressing AML1 target gene expression (6), the molecular mechanism of action of AML1-ETO is likely to be more complex since it can both repress or promote transcription depending on the target genes and the cellular context (7).To gain insights into the function and mode of action of AML1-ETO, several animal models for t(8;21) leukemia have been developed using bone marrow transplantation, knock-in or transgenic techniques (8). These models supported the hypothesis that AML1-ETO dominantly suppresses the function of the endogenous AML1 protein in vivo (9-11). In addition, these works indicate that AML1-ETO inhibits myeloid differentiation and promotes self-renewal of hematopoietic progenitors (12-16)...

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“…AML1 is also fused to TEL as a result of t (12;21) in approximately 25% of childhood leukemia, the most common form of childhood cancers. Although animal modeling clearly indicates that AML1 fusions per se are not sufficient for induction of full-blown leukemia, they function to enhance self-renewal and expand targeted HSCs and early progenitors for cooperative secondary mutations to take place (3)(4)(5).…”

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confidence: 99%

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

Kwok

Zeisig

Qiu

et al. 2009

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

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Although both heterodimeric subunits of core binding factors (AML1/RUNX1 and CBF␤) essential for normal hematopoiesis are frequently mutated to form different chimeric fusion proteins in acute leukemia, the underlying molecular mechanisms and structural domains required for cellular transformation remain largely unknown. Despite the critical role of CBF␤ for wild-type AML1 function and its direct involvement in chromosomal translocation, we demonstrate that both the expression and interaction with CBF␤ are superfluous for AML1-ETO (AE)-mediated transformation of primary hematopoietic cells. Similarly, the hetero-oligomeric interaction with transcriptional repressor ETO family proteins and the highly conserved NHR1 domain in AE fusion are also dispensable for transforming activity. In contrast, AE-mediated transformation is critically dependent on the DNA binding and homo-oligomeric properties of the fusion. Abolishment of homooligomerization by a small-molecule inhibitor could specifically suppress AML1 fusion-mediated transformation of primary hematopoietic cells. Together, these results not only identify the essential molecular components but also potential avenues for therapeutic targeting of AE-mediated leukemogenesis.A ML1/RUNX1 and CBF␤ are 2 critical transcription factors essential for generation of hematopoietic stem cells (HSCs) (1, 2). Mice deficient in AML1 or CBF␤ have almost identical phenotypes; they completely lack definitive hematopoiesis and die at approximately embryonic day 12.5. In acute myeloid leukemia in which leukemic stem cells have been functionally identified, AML1 and CBF␤ represent the most commonly mutated targets (1, 2). t(8;21) resulting in AML1-ETO (AE) fusion can be found in up to 40% of AML-M2; and inv(16) leading to CBF␤-SHMMC fusion constitutes approximately 30% of AML-M4. AML1 is also fused to TEL as a result of t(12;21) in approximately 25% of childhood leukemia, the most common form of childhood cancers. Although animal modeling clearly indicates that AML1 fusions per se are not sufficient for induction of full-blown leukemia, they function to enhance self-renewal and expand targeted HSCs and early progenitors for cooperative secondary mutations to take place (3-5).While enhanced self-renewal has emerged as a critical feature associated with various oncogenic transcription factors involved in acute leukemia (6-8), much less is known about the underlying molecular mechanisms. It is clear that most, if not all, of the transcription factors do not work as monomers but need to complex with various proteins for full activity and specificity, although the molecular composition of the associated transcriptional complexes required for self-renewal remains largely unknown. At the molecular level, AE encodes the DNA-binding runt homology domain (RHD) fused in-frame with almost the entire transcriptional repressor protein ETO containing 4 different Nervy homology regions (NHRs) (Fig. 1A), suggesting a gain of transcriptional repressor function by the oncogenic fusion (9). A well-reco...

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Review: genetic models of acute myeloid leukaemia

Cited by 46 publications

References 111 publications

Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

Anti-leukemic activity of Lintuzumab (SGN-33) in preclinical models of acute myeloid leukemia

A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO

Transforming activity of AML1-ETO is independent of CBFβ and ETO interaction but requires formation of homo-oligomeric complexes

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