Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice

Cuenco, Grace M; Ren, Ruibao

doi:10.1038/sj.onc.1207143

Cited by 43 publications

(45 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EVI1 is an oncogene that is frequently associated with acute and chronic myelogenous leukemia (43)(44)(45) and has also been Figure 6. Knockdown of DACH1 expression partially restores TGF-h signaling in A547 cells.…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde

Donninger²,

et al. 2006

Cancer Research

View full text Add to dashboard Cite

Ovarian cancer is resistant to the antiproliferative effects of transforming growth factor-B (TGF-B); however, the mechanism of this resistance remains unclear. We used oligonucleotide arrays to profile 37 undissected, 68 microdissected advanced-stage, and 14 microdissected early-stage papillary serous cancers to identify signaling pathways involved in ovarian cancer. A total of seven genes involved in TGF-B signaling were identified that had altered expression >1.5-fold (P < 0.001) in the ovarian cancer specimens compared with normal ovarian surface epithelium. The expression of these genes was coordinately altered: genes that inhibit TGF-B signaling (DACH1, BMP7, and EVI1) were up-regulated in advanced-stage ovarian cancers and, conversely, genes that enhance TGF-B signaling (PCAF, TFE3, TGFBRII, and SMAD4) were down-regulated compared with the normal samples. The microarray data for DACH1 and EVI1 were validated using quantitative real-time PCR on 22 microdissected ovarian cancer specimens. The EVI1 gene locus was amplified in 43% of the tumors, and there was a significant correlation (P = 0.029) between gene copy number and EVI1 gene expression. No amplification at the DACH1 locus was found in any of the samples. DACH1 and EVI1 inhibited TGF-B signaling in immortalized normal ovarian epithelial cells, and a dominant-negative DACH1, DACH1-#DS, partially restored signaling in an ovarian cancer cell line resistant to TGF-B. These results suggest that altered expression of these genes is responsible for disrupted TGF-B signaling in ovarian cancer and they may be useful as new and novel therapeutic targets for ovarian cancer. (Cancer Res 2006; 66(17): 8404-12)

show abstract

Section: Discussionmentioning

confidence: 99%

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Sunde

Donninger²,

et al. 2006

Cancer Research

View full text Add to dashboard Cite

show abstract

“…The human AME, MDS1/EVI1, EVI1, AML1/MDS1, and AML1D genes were each cloned into a bicistronic murine stem cell virus (MSCV) vector downstream of the encephalomyocarditis virus internal ribosomal entry site (IRES) and two myc tag sequences as described previously (2,20). An enhanced green fluorescent protein (GFP) gene was cloned into the EcoRI site upstream of the IRES on the MSCV vector.…”

Section: Methodsmentioning

confidence: 99%

“…Experiments in vitro showed that overexpression of the EVI1 protein blocks granulocytic differentiation of the myeloid precursor cell line 32Dcl3, inhibits erythropoietic responsiveness in erythroid progenitors, and up-regulates the megakaryocytic differentiation of murine embryonic stem cells (16)(17)(18). In vivo, enforced expression of EVI1 using the murine Sca-1 promoter in transgenic mice impairs normal erythropoiesis and expression of EVI1 in bone marrow cells by retroviral transduction and transplantation induces either B-lymphoid malignancy with low efficiency or severe pancytopenia resembling MDS after a long latent period (19)(20)(21). These results show that aberrant expression of the EVI1 proto-oncogene plays a critical role in the pathogenesis of hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

Targeted Degradation of the AML1/MDS1/EVI1 Oncoprotein by Arsenic Trioxide

et al. 2006

Self Cite

View full text Add to dashboard Cite

Arsenic trioxide (ATO) has been found to be an effective treatment for acute promyelocytic leukemia patients and is being tested for treating other hematologic malignancies. We have previously shown that AML1/MDS1/EVI1 (AME), a fusion gene generated by a t(3;21)(q26;q22) translocation found in patients with chronic myelogenous leukemia during blast phase, myelodysplastic syndrome, or acute myelogenous leukemia (AML), impairs hematopoiesis and eventually induces an AML in mice. Both fusion partners of AME, AML1 and MDS1/EVI1, encode transcription factors and are also targets of a variety of genetic abnormalities in human hematologic malignancies. In addition, aberrant expression of ectopic viral integration site 1 (EVI1) has also been found in solid tumors, such as ovarian and colon cancers. In this study, we examined whether ATO could target AME and related oncoproteins. We found that ATO used at therapeutic levels degrades AME. The ATO treatment induces differentiation and apoptosis in AME leukemic cells in vitro as well as reduces tumor load and increases the survival of mice transplanted with these cells. We further found that ATO targets AME via both myelodysplastic syndrome 1 (MDS1) and EVI1 moieties and degrades EVI1 via the ubiquitin-proteasome pathway and MDS1 in a proteasome-independent manner. Our results suggest that ATO could be used as a part of targeted therapy for AME-, AML1/MDS1-, MDS1/EVI1-, and EVI1-positive human cancers. (Cancer Res 2006; 66(23): 11360-9)

show abstract

“…41 In these studies, however, a potential confounding role of the vector insertion site was not addressed. Other studies speculate on necessary cooperation partners for leukemia induction by Evi1.…”

Section: Single Hit Leukemias Are Caused By Insertional Upregulation mentioning

confidence: 99%

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

et al. 2008

View full text Add to dashboard Cite

Insertional activation of cellular proto-oncogenes by replication-defective retroviral vectors can trigger clonal dominance and leukemogenesis in animal models and clinical trials. Here, we addressed the leukemogenic potential of vectors expressing interleukin-2 receptor common c-chain (IL2RG), the coding sequence required for correction of X-linked severe combined immunodeficiency. Similar to conventional c-retroviral vectors, self-inactivating (SIN) vectors with strong internal enhancers also triggered profound clonal imbalance, yet with a characteristic insertion preference for a window located downstream of the transcriptional start site. Controls including lentivirally transduced cells revealed that ectopic IL2RG expression was not sufficient to trigger leukemia. After serial bone marrow transplantation involving 106 C57Bl6/J mice monitored for up to 18 months, we observed leukemic progression of six distinct clones harboring c-retroviral long terminal repeat (LTR) or SIN vector insertions in Evi1 or Prdm16, two functionally related genes. Three leukemic clones had single vector integrations, and identical clones manifested with a remarkably similar latency and phenotype in independent recipients. We conclude that upregulation of Evi1 or Prdm16 was sufficient to initiate a leukemogenic cascade with consistent intrinsic dynamics. Our study also shows that insertional mutagenesis is required for leukemia induction by IL2RG vectors, a risk to be addressed by improved vector design.

show abstract

Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice

Cited by 43 publications

References 45 publications

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Expression Profiling Identifies Altered Expression of Genes That Contribute to the Inhibition of Transforming Growth Factor-β Signaling in Ovarian Cancer

Targeted Degradation of the AML1/MDS1/EVI1 Oncoprotein by Arsenic Trioxide

Leukemia induction after a single retroviral vector insertion in Evi1 or Prdm16

Contact Info

Product

Resources

About