The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia

Castilla, Lucio H.; Garrett, Lisa; Adya, Neeraj; Orlic, Donald; Dutra, Amalia; Anderson, Stacie M.; Owens, Jennie W.; Eckhaus, Michael; Bodine, David M.; Liu, P. Paul

doi:10.1038/13776

Cited by 270 publications

(244 citation statements)

References 15 publications

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“…It may be a common underlying mechanism for the pathogenesis in AML1-associated leukemia. However, recently generated transgenic or knock-in mice showed that AML1 mutations are critical for the development of AML, but that one or more additional mutations are necessary for leukemogenesis [10][11][12]. This accepted hypothesis is supported by the cytogenetic findings in the case of our patient exhibiting a complex karyotype.…”

supporting

confidence: 70%

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

et al. 2009

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supporting

confidence: 70%

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

et al. 2009

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“…CBFb-SMMHC prevents the development of de®nitive hematopoiesis during murine embryogenesis and obviates the formation of lymphoid and myeloid cells in adult mice (Castilla et al, 1996(Castilla et al, , 1999. The ability of CBFb-SMMHC to inhibit cell cycle progression might account for these phenotypes (Cao et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Exogenous cdk4 overcomes reducedcdk4 RNA and inhibition of G1 progression in hematopoietic cells expressing a dominant-negative CBF – a model for overcoming inhibition of proliferation by CBF oncoproteins

Lou¹,

Cao²,

Bernardin³

et al. 2000

Oncogene

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Core Binding Factor (CBF) is required for the development of de®nitive hematopoiesis, and the CBF oncoproteins AML1-ETO, TEL-AML1, and CBFb-SMMHC are commonly expressed in subsets of acute leukemia. CBFb-SMMHC slows the G1 to S cell cycle transition in hematopoietic cells, but the mechanism of this e ect is uncertain. We have sought to determine whether inhibition of CBF-mediated trans-activation is su cient to slow proliferation. We demonstrate that activation of KRAB-AML1-ER, a protein containing the AML1 DNA-binding domain, the KRAB repression domain, and the Estrogen receptor ligand binding domain, also slows G1, if its DNA-binding domain is intact. Also, exogenous AML1 overcame CBFb-SMMHC-induced inhibition of proliferation. Representational di erence analysis (RDA) identi®ed cdk4 RNA expression as an early target of KRAB-AML1 activation. Inhibition of CBF activities by KRAB-AML1-ER or CBFb-SMMHC rapidly reduced endogenous cdk4 mRNA levels, even in cells proliferating at or near control rates as a result of exogenous cdk4 expression. Over-expression of cdk4, especially a variant which cannot bind p16 INK4a , overcame cell cycle inhibition resulting from activation of KRAB-AML1-ER, although cdk4 did not accelerate proliferation when expressed alone. These ®ndings indicate that mutations which alter the expression of G1 regulatory proteins can overcome inhibition of proliferation by CBF oncoproteins.

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“…However, 84% of CBFb þ /CBFbÀMYH11 chimeras (Castilla et al, 1999), which do not develop leukaemia in their first year of life, died from AML FAB M4 (that is myelomonocytic variant)-type disease when administered a single dose of ENU 2-6 months after treatment. In contrast, none of the wild-type chimeras treated with ENU developed disease, concluding that CBFb-MYH11 blocks differentiation, but cooperation with further oncogenes is necessary for leukaemogenesis.…”

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 fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia

Cited by 270 publications

References 15 publications

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

Hereditary thrombocytopenia and acute myeloid leukemia: a common link due to a germline mutation in the AML1 gene

Exogenous cdk4 overcomes reducedcdk4 RNA and inhibition of G1 progression in hematopoietic cells expressing a dominant-negative CBF – a model for overcoming inhibition of proliferation by CBF oncoproteins

Review: genetic models of acute myeloid leukaemia

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