Deregulated TGF-β signaling in leukemogenesis

Lin, Hui Kuan; Bergmann, Stephan; Pandolfi, Pier Paolo

doi:10.1038/sj.onc.1208923

Cited by 44 publications

(40 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several myeloid leukemia-associated fusion genes, including AML1-ETO (27), AML1-EVI1 (43), and (41), appear to block the growth-inhibiting properties of TGF-β1, and there may be a loss of TGF-β1 type I receptors in a fraction of chronic lymphocytic leukemias (44).…”

Section: Discussionmentioning

confidence: 99%

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

Ford¹,

Palmi²,

Bueno³

et al. 2009

J. Clin. Invest.

110

View full text Add to dashboard Cite

Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-β. This facilitates the competitive expansion of TEL-AML1-expressing cells in the presence of TGF-β. Further analysis indicated that TEL-AML1 binds to a principal TGF-β signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-β-mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34 + CD38 -CD19 + ) and a marked growth advantage in the presence of TGF-β. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1-expressing preleukemic clones.

show abstract

Section: Discussionmentioning

confidence: 99%

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

Ford¹,

Palmi²,

Bueno³

et al. 2009

J. Clin. Invest.

110

View full text Add to dashboard Cite

show abstract

“…Impaired TGF␤ signaling has been implicated in tumorigenesis, including hematopoietic and epithelial malignancies (34,39). Notably, p15 INK4B represents an important effector of TGF␤-induced growth arrest.…”

Section: Discussionmentioning

confidence: 99%

Gfi-1 represses CDKN2B encoding p15 ^INK4B through interaction with Miz-1

Basu

Liu

Qiu

et al. 2009

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

View full text Add to dashboard Cite

Gfi-1 is a nuclear zinc finger (ZF) transcriptional repressor that plays an important role in hematopoiesis and inner ear development, and has been implicated in lymphomagenesis. Gfi-1 represses transcription by directly binding to the consensus DNA sequence in the promoters of its target genes. We report here an alternative mechanism by which Gfi-1 represses CDKN2B encoding p15 INK4B . Gfi-1 does not directly bind to CDKN2B, but interacts with Miz-1 and, via Miz-1, is recruited to the core promoter of CDKN2B. Miz-1 is a POZ-ZF transcription factor that has been shown to mediate transcriptional repression by c-Myc. Like c-Myc, upon recruitment to the CDKN2B promoter, Gfi-1 represses transcriptional activation of CDKN2B by Miz-1 and in response to TGF␤. Consistent with its role in repressing CDKN2B transcription, knockdown of Gfi-1 in human leukemic cells or deficiency of Gfi-1 in mouse bone marrow cells results in augmented expression of p15 INK4B . Notably, Gfi-1 and c-Myc are both recruited to the CDKN2B core promoter and act in collaboration to repress CDKN2B. Our data reveal a mechanism of transcriptional repression by Gfi-1 and may have important implications for understanding the roles of Gfi-1 in normal development and tumorigenesis.cyclin-dependent kinase inhibitor ͉ proliferation ͉ transcriptional repressor ͉ tumorigenesis

show abstract

“…on cell growth and death, whereby the outcome of these opposing effects depends on cellular context and environmental factors (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells

et al. 2007

View full text Add to dashboard Cite

show abstract

Deregulated TGF-β signaling in leukemogenesis

Cited by 44 publications

References 66 publications

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

Gfi-1 represses CDKN2B encoding p15 ^INK4B through interaction with Miz-1

Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells

Contact Info

Product

Resources

About

Deregulated TGF-β signaling in leukemogenesis

Cited by 44 publications

References 66 publications

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

The TEL-AML1 leukemia fusion gene dysregulates the TGF-β pathway in early B lineage progenitor cells

Gfi-1 represses CDKN2B encoding p15 INK4B through interaction with Miz-1

Signal Transducer and Activator of Transcription 1 Regulates Both Cytotoxic and Prosurvival Functions in Tumor Cells

Contact Info

Product

Resources

About

Gfi-1 represses CDKN2B encoding p15 ^INK4B through interaction with Miz-1