Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma

Mallo, Mar; Espinet, Blanca; Salido, Marta; Ferrer, Ana; Pedro, Carmen; Besses, Carles; Pérez-Vila, Encarna; Serrano, Sergi; Florensa, Lourdes; Solé, Françesc

doi:10.1016/j.cancergencyto.2007.07.018

Cited by 6 publications

(4 citation statements)

References 18 publications

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“…Our study is the first to demonstrate that the tumorigenicity of prostate and ovarian cells requires CBFβ. The present findings are consistent with those from previous studies demonstrating that CBFβ is required for AML‐1/ETO and TEL‐AML‐1 activity, and that it is amplified in granulocytic sarcoma, collectively demonstrating that CBFβ is intimately associated with the cellular pathways that regulate carcinogenesis (Mallo et al, 2007; Roudaia et al, 2009). Given the diversity of cell types that express CBFβ, we expect that CBFβ participates in pathways essential to a wide variety of cancers.…”

Section: Discussionsupporting

confidence: 93%

“…In contrast, other studies have demonstrated that CBF possesses oncogenic attributes (Ito, 2004). For example, the genes encoding RUNX1 and CBFβ are amplified in human B‐cell ALL and granulocytic sarcoma, respectively, and RUNX3 is over‐expressed in human ovarian cancers and basal cell carcinomas (Niini et al, 2000; Salto‐Tellez et al, 2006; Mallo et al, 2007; Nevadunsky et al, 2009). Amplification and over‐expression are generally considered hallmarks of an oncogene, suggesting that CBF can be oncogenic.…”

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confidence: 99%

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Association of core‐binding factor β with the malignant phenotype of prostate and ovarian cancer cells

Davis

Rogers

Adams

et al. 2010

Journal Cellular Physiology

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Core binding factor (CBF) is a transcription factor complex that plays roles in development, stem-cell homeostasis, and human disease. CBF is a heterodimer composed of one of three DNA-binding RUNX proteins plus the non-DNA-binding protein, CBFβ. Recent studies have showed that the RUNX factors exhibit complex expression patterns in prostate, breast, and ovarian cancers, and CBF has been implicated in the control of cancer-related genes. However, the biologic roles of CBF in solid tumors have not been fully elucidated. To test whether CBF is required for the malignant phenotype of various epithelial cancers, we used lentiviral delivery of CBFβ-specific shRNA to significantly decrease CBFβ expression in two prostate cancer cell lines (PPC1 and PC-3) and the SKOV-3 ovarian cancer cell line. We found that knockdown of CBFβ significantly inhibited anchorage independent growth of each cell line. Further, CBFβ knockdown in PPC1 cells suppressed xenograft tumor growth compared to controls. Mice injected with SKOV-3 ovarian cancer cells knocked-down for CBFβ exhibited a survival time similar to control mice. However, human cells recovered from the ascites fluid of these mice showed CBFβ expression levels similar to those from mice injected with control SKOV-3 cells, suggesting that CBFβ knockdown is incompatible with tumor cell growth. Gene expression profiling of CBFβ knockdown cells revealed significant changes in expression in genes involved in various developmental and cell signaling pathways. These data collectively suggest that CBFβ is required for malignancy in some human cancers.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Association of core‐binding factor β with the malignant phenotype of prostate and ovarian cancer cells

Davis

Rogers

Adams

et al. 2010

Journal Cellular Physiology

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“…On the other hand, no genetic defects have been described for CBFβ in osteosarcoma yet. However, there is a report of multiple CBFβ gene copies detected by FISH in a single case of granulocytic sarcoma associated with myeloid leukemia (Mallo et al, 2007). …”

Section: Discussionmentioning

confidence: 99%

Impaired cell cycle regulation of the osteoblast‐related heterodimeric transcription factor Runx2‐Cbfβ in osteosarcoma cells

Martin

Varela

Gaete

et al. 2009

Journal Cellular Physiology

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In mammals, bone differentiation requires the functional expression of the Runx2/Cbfβ heterodimeric complex. Our previous results indicate that Runx2 is also a suppressor of preosteoblast proliferation by affecting cell cycle progression at G 1 . Runx2 levels are cell cycle regulated, oscillating from a maximum during early G 1 to a minimum during late G 1 , S and mitosis phases in proliferating pre-osteoblasts Nevertheless, there is no information concerning Cbfβ gene expression during the cell cycle nor on Runx2 cell cycle expression in bone cancer cells. We analyzed Runx2 and Cbfβ gene expression during cell cycle progression in the preosteoblast MC3T3 and osteosarcoma ROS and SaOS cell lines. The expected reduction of Runx2 protein level was observed in MC3T3 cells arrested in late G 1 or M phase using mimosine or nocodazole, respectively. However, this reduction was not observed in the cell cycle arrested osteosarcoma cells. Cbfβ protein levels were not regulated during the cell cycle in pre-osteoblasts and osteosarcoma cells. Using cells synchronized in late G 1 and mitosis we found that Runx2 levels, but not Cbfβ levels, were cell cycle regulated in MC3T3 osteoblasts. Interestingly, both factors showed a constitutively elevated expression throughout the cell cycle in osteosarcoma cells. Proteasome inhibition by MG132 prevented cell cycle-dependent downregulation of Runx2 protein levels in osteoblasts, but not in osteosarcoma. We propose that Runx2 is involved in tumoral osteosarcoma progression. Altogether, deregulated Runx2 expression throughout the cell cycle seems to constitute a central mechanism in the pathogenesis of osteosarcoma.

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“…CBFβ is the most frequently mutated and rearranged gene in human leukemias and plays an important role in hematologic malignancies [33, 55, 58]. Although no genetic defects have been reported for CBFβ in other types of human cancers, such as in osteosarcoma, there is a report of multiple CBFβ gene copies detected by FISH in a single case of granulocytic sarcoma associated with myeloid leukemia [59]. In line with previous gene profiling, high expression of CBFβ mRNA has been found in KHOS and U-2OS cell lines, and the expression of CBFβ is CDK11 expression dependent.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

et al. 2019

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Background Aberrant expression of cyclin-dependent protein kinases (CDK) is a hallmark of cancer. CDK11 plays a crucial role in cancer cell growth and proliferation. However, the molecular mechanisms of CDK11 and CDK11 transcriptionally regulated genes are largely unknown. Methods In this study, we performed a global transcriptional analysis using gene array technology to investigate the transcriptional role of CDK11 in osteosarcoma. The promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay were used to identify direct transcriptional targets of CDK11. Clinical relevance and function of core-binding factor subunit beta (CBFβ) were further accessed in osteosarcoma. Results We identified a transcriptional role of protein-DNA interaction for CDK11p110, but not CDK11p58, in the regulation of CBFβ expression in osteosarcoma cells. The CBFβ promoter luciferase assay, chromatin immunoprecipitation assay, and Gel Shift assay confirmed that CBFβ is a direct transcriptional target of CDK11. High expression of CBFβ is associated with poor outcome in osteosarcoma patients. Expression of CBFβ contributes to the proliferation and metastatic behavior of osteosarcoma cells. Conclusions These data establish CBFβ as a mediator of CDK11p110 dependent oncogenesis and suggest that targeting the CDK11- CBFβ pathway may be a promising therapeutic strategy for osteosarcoma treatment. Graphical Abstract

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Gain of multiple copies of the CBFB gene: a new genetic aberration in a case of granulocytic sarcoma

Cited by 6 publications

References 18 publications

Association of core‐binding factor β with the malignant phenotype of prostate and ovarian cancer cells

Association of core‐binding factor β with the malignant phenotype of prostate and ovarian cancer cells

Impaired cell cycle regulation of the osteoblast‐related heterodimeric transcription factor Runx2‐Cbfβ in osteosarcoma cells

Transcriptional activation of CBFβ by CDK11p110 is necessary to promote osteosarcoma cell proliferation

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