A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC

Vaillant, François; Blyth, Karen; Terry, Anne; Bell, Margaret; Cameron, Ewan R.; Neil, James C.; Stewart, Monica

doi:10.1038/sj.onc.1203202

Cited by 80 publications

(95 citation statements)

References 43 publications

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“…Sustained expression of Runx2 alters T cell activation (31,32), whereas MLV insertions upstream of Runx2 induce lymphomagenesis in cooperation with Myc (14,33,34). In our study, however, three insertions (Cri48) mapped within Runx2 intron 5.…”

Section: Candidate Genes That Synergize With Cbfb-myh11 In Leukemogenmentioning

confidence: 39%

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia

Castilla

Perrat

Martínez

et al. 2004

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

116

110

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Acute myeloid leukemia subtype M4 with eosinophilia is associated with a chromosome 16 inversion that creates a fusion gene CBFB-MYH11. We have previously shown that CBFB-MYH11 is necessary but not sufficient for leukemogenesis. Here, we report the identification of genes that specifically cooperate with CBFB-MYH11 in leukemogenesis. Neonatal injection of Cbfb-MYH11 knock-in chimeric mice with retrovirus 4070A led to the development of acute myeloid leukemia in 2-5 months. Each leukemia sample contained one or a few viral insertions, suggesting that alteration of one gene could be sufficient to synergize with Cbfb-MYH11. The chromosomal position of 67 independent retroviral insertion sites (RISs) was determined, and 90% of the RISs mapped within 10 kb of a flanking gene. In total, 54 candidate genes were identified; six of them were common insertion sites (CISs). CIS genes included members of a zinc finger transcription factors family, Plag1 and Plagl2, with eight and two independent insertions, respectively. CIS genes also included Runx2, Myb, H2-T24, and D6Mm5e. Comparison of the remaining 48 genes with single insertion sites with known leukemia-associated RISs indicated that 18 coincide with known RISs. To our knowledge, this retroviral genetic screen is the first to identify genes that cooperate with a fusion gene important for human myeloid leukemia.

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Section: Candidate Genes That Synergize With Cbfb-myh11 In Leukemogenmentioning

confidence: 39%

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia

Castilla

Perrat

Martínez

et al. 2004

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

116

110

View full text Add to dashboard Cite

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“…Insufficient downregulation of RUNX1 due to the increased dose at a certain stage of megakaryocyte differentiation may result in disturbed regulation of cell proliferation and could eventually give rise to TAM, then leukemia. Consistent with this notion, Runx2 Tg mice which overexpress Runx2 also showed impaired differentiation of T-cell or bone development (Vaillant et al, 1999;Liu et al, 2001). On the other hand, another mechanism, a constitutive expression of RUNX1 that may be caused by an increased dose should be considered carefully, since RUNX1 is shown to be regulated in a cell-cycledependent manner (Bernardin-Fried et al, 2004).…”

Section: Discussionmentioning

confidence: 50%

Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice

et al. 2005

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The RUNX1/AML1 gene on chromosome 21 is most frequently inactivated in human leukemias. In addition, an increased dose of RUNX1 is suggested as a basis for several kinds of leukemias. Amplifications of chromosome 21 or the RUNX1 gene are shown to be associated with leukemias with lymphoid lineage, whereas its involvement in myeloid lineage remains unclear. In this study, we generated GATA-1 promoter-driven Runx1 transgenic (Tg) mice, which showed a transient mild increase of megakaryocyte marker-positive myeloid cells but no spontaneous leukemia. These mice were then crossed with BXH2 mice, which have a replication-competent retrovirus in the mouse and develop myeloid leukemia due to insertional mutagenesis by random integration of the virus. Overexpressed Runx1 transgene in BXH2 mice resulted in shortening of the latency of leukemia with increased frequency of megakaryoblastic leukemia, suggesting that increased Runx1 dosage is leukemogenic in myeloid lineage. Identifications of retroviral integration sites revealed the genetic alterations that may cooperate with Runx1 overdose in myeloid leukemogenesis. This mouse model may be useful for analysing the pathogenesis of myeloid leukemias with RUNX1 overdose, especially to examine whether an extra-copy of RUNX1 by trisomy 21 is causally related to Down's syndrome-related acute megakaryoblastic leukemia (DS-AMKL).

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“…Ectopic overexpression of p53 by adenoviral delivery to EC also increased p21 CIP1 expression and interfered with EC differentiation (Riccioni et al, 1998). The c-myc proto-oncogene represses p21 CIP1 expression (Claassen and Hann, 2000) and Runx2 transgenic mice develop lymphomas in association with c-myc (Stewart et al, 1997;Vaillant et al, 1999), suggesting that RUNX2 may regulate downstream targets much like c-myc . The related RUNX1 gene has been shown to act as a transcriptional activator of the cdk inhibitor p14 ARF , which induces cellular senescence in lymphoid cells (Linggi et al, 2002), whereas AML1-ETO is a strong transcriptional repressor of the p14 ARF promoter and inactivates the p14 ARF tumor suppressor gene.…”

Section: Transcriptional Repression Of the P21 Cip1 Promotermentioning

confidence: 99%

Regulation of TGFβ1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells

et al. 2004

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Runx transcription factors regulate viral growth, hematopoiesis, bone formation, angiogenesis, and gastric epithelial development through specific DNA-binding motifs on target gene promoters. Vascular endothelial cells (ECs) express RUNX genes that are activated by angiogenic factors. The RUNX2 gene also activates the vascular endothelial growth factor promoter. Alternatively spliced forms of RUNX genes have been described, but their functions in angiogenesis have not been elucidated. In this study, expression of a novel alternatively spliced variant of RUNX2 (RUNX2D8), lacking the region encoded by exon 8, was detected in aortic tissue undergoing angiogenesis in vitro and in ECs. Expression of RUNX2 and RUNX2D8 increased in vascular sprouts concomitant with expression of cellular proteases and cytokines known to mediate angiogenesis. RUNX2 DNA-binding activity was expressed in proliferating but not quiescent ECs. Ectopic expression of RUNX2 in ECs increased cell sprouting, cell proliferation, DNA synthesis, and phosphorylation of phosphorylated retinoblastoma relative to control transfectants while RUNX2, but not RUNX2D8 transfectants, acquired resistance to growth inhibition by transforming growth factor (TGFb 1 ). Furthermore, RUNX2D8-transfected cells were more sensitive to TGFb 1 -induced apoptosis than RUNX2 transfectants. Consistent with these data, the RUNX2 gene was a strong repressor of the promoter of the cyclin-dependent kinase inhibitor, p21 CIP1 , while RUNX2D8 was a competitive inhibitor of RUNX2 and exhibited weak repression activity. These results support the hypothesis that ECs regulate growth and apoptosis, in part, by alternative splicing events in the RUNX2 transcription factor to affect the TGFb 1 signaling pathway. The exon 8 domain of RUNX2 may contribute to the strong repression activity of RUNX2 for some target gene promoters.

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A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with MYC

Cited by 80 publications

References 43 publications

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia

Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia

Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice

Regulation of TGFβ1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells

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