Runx2: A novel oncogenic effector revealed by in vivo complementation and retroviral tagging

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

doi:10.1038/sj.onc.1204090

Cited by 100 publications

(112 citation statements)

References 47 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: 40%

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

109

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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: 40%

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

109

View full text Add to dashboard Cite

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“…Although Runx2 is expressed in cells of the osteoblast lineage throughout skeletal development, its levels increase only 1.5-2-fold as preosteoblasts differentiate into mature osteoblasts. Furthermore, the amount of Runx2 bound to target promoters, as measured by chromatin immunoprecipitation, is relatively unchanged throughout differentiation (6), yet the targets it regulates have distinct patterns of expression. These observations suggest that the regulation of Runx2 activity, either by post-translational modification or by the binding of co-regulators, plays a substantial role in defining the Runx2-mediated activation of target genes.…”

mentioning

confidence: 99%

Identification of the GATA Factor TRPS1 as a Repressor of the Osteocalcin Promoter

Piscopo

Johansen

Derynck

2009

Journal of Biological Chemistry

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A proteomic analysis of proteins bound to the osteocalcin OSE2 sequence of the mouse osteocalcin promoter identified TRPS1 as a regulator of osteocalcin transcription. Mutations in the TRPS1 gene are responsible for human tricho-rhino-phalangeal syndrome, which is characterized by skeletal and craniofacial abnormalities. TRPS1 has been shown to bind regulatory promoter sequences containing GATA consensus binding sites and to repress transcription of genes involved in chondrocyte differentiation. Here we show that TRPS1 can directly bind the osteocalcin promoter in the presence or absence of Runx2. TRPS1 binds through a GATA binding sequence in the proximal promoter of the osteocalcin gene. The GATA binding site is conserved in mice, humans, and rats, although its location and orientation are not. Mutation of the mouse or human GATA binding sequence abrogates binding of TRPS1 to the osteocalcin promoter. We show that TRPS1 is expressed in osteosarcoma cells and upon induction of osteoblast differentiation in primary mouse bone marrow stromal cells and that TRPS1 regulates the expression of osteocalcin in both cell types. The expression of TRPS1 modulates mineralized bone matrix formation in differentiating osteoblast cells. These data suggest a role for TRPS1 in osteoblast differentiation, in addition to its previously described role in chondrogenesis.Runx2, previously described as CBFA1, OSF2, AML3, or PEPB2␣A, is a runt homology domain transcription factor and plays a key role in driving osteoblast differentiation. Runx2 expression, which occurs in differentiating and mature osteoblasts, is essential for bone formation, as illustrated by the phenotype of Runx2-deficient mice, which lack osteoblasts and have skeletons that are primarily composed of immature chondrocytes (1-3). Haploinsufficiency for RUNX2 in humans results in cleidocranial dysplasia, a syndrome that is characterized by delayed endochondral and intramembranous ossification (4). Runx2 transactivates genes involved in the deposition of bone matrix, e.g. those encoding osteocalcin, collagen IA1, osteopontin, and matrix metalloproteinase 13 (MMP13), and regulation of osteoclastogenesis, e.g. the genes encoding RankL and osteoprotegerin (reviewed in Ref. 5). Although Runx2 is expressed in cells of the osteoblast lineage throughout skeletal development, its levels increase only 1.5-2-fold as preosteoblasts differentiate into mature osteoblasts. Furthermore, the amount of Runx2 bound to target promoters, as measured by chromatin immunoprecipitation, is relatively unchanged throughout differentiation (6), yet the targets it regulates have distinct patterns of expression. These observations suggest that the regulation of Runx2 activity, either by post-translational modification or by the binding of co-regulators, plays a substantial role in defining the Runx2-mediated activation of target genes. Various proteins have been shown to interact with Runx2 and modulate its activity, including Smad3, CREB 2 -binding protein (CBP) HES1, Groucho/TLE, and histone d...

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“…Runx2 (also known as Cbfa1 or AML3) displays extensive sequence similarity to Runx1, and functions as a novel oncogenic eector for T-cell lymphoma (Vaillant et al, 1999;Blyth et al, 2001). Runx2 also plays an essential role in controlling osteoblast dierentiation and bone formation (Ducy et al, 2000;Wheeler et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2

et al. 2002

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The monocytic leukemia zinc ®nger protein MOZ and its homologue MORF have been implicated in leukemogenesis. Both MOZ and MORF are histone acetyltransferases with weak transcriptional repression domains and strong transcriptional activation domains, suggesting that they may function as transcriptional coregulators. Here we describe that MOZ and MORF both interact with Runx2 (or Cbfa1), a Runt-domain transcription factor that is known to play important roles in T cell lymphomagenesis and bone development. Through its C-terminal SM (serine-and methioninerich) domain, MORF binds to Runx2 in vitro and in vivo. Consistent with this, the SM domain of MORF also binds to Runx1 (or AML1), a Runx2 homologue that is frequently altered by leukemia-associated chromosomal translocations. While MORF does not acetylate Runx2, its SM domain potentiates Runx2-dependent transcriptional activation. Moreover, endogenous MORF is required for transcriptional activation by Runx2. Intriguingly, Runx2 negatively regulates the transcriptional activation potential of the SM domain. Like that of MORF, the SM domain of MOZ physically and functionally interacts with Runx2. These results thus identify Runx2 as an interaction partner of MOZ and MORF and suggest that both acetyltransferases are involved in regulating transcriptional activation mediated by Runx2 and its homologues.

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Runx2: A novel oncogenic effector revealed by in vivo complementation and retroviral tagging

Cited by 100 publications

References 47 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

Identification of the GATA Factor TRPS1 as a Repressor of the Osteocalcin Promoter

MOZ and MORF histone acetyltransferases interact with the Runt-domain transcription factor Runx2

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