The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans

Carrasco, Daniel R.; Fenton, Tim R.; Sukhdeo, Kumar; Protopopova, Marina; Enos, Miriam; You, M. James; Divicio, Dolores; Nogueira, Cristina; Stommel, Jayne M.; Pinkus, Geraldine S.; Fletcher, Christopher D.�M.; Hornick, Jason L.; Cavenee, Webster K.; Furnari, Frank B.; DePinho, Ronald A.

doi:10.1016/j.ccr.2006.03.028

Cited by 59 publications

(56 citation statements)

References 49 publications

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“…2 B and C). With regard to tumor spectrum, early generation mTerc Ink4a/Arf mutant mice with intact telomeres succumbed largely to the previously reported Ink4a/Arf mutant profile of histiocytic sarcomas (34),** soft tissue sarcomas, and lymphomas (33,35,36). Comparison of early and late-generation mTercϪ/Ϫ Ink4a/ Arfϩ/Ϫ mice showed no significant changes in tumor spectrum.…”

Section: Ink4amentioning

confidence: 88%

Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse

Khoo

Carrasco

Bosenberg

et al. 2007

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

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The Rb/p16 Ink4a and p53/p19Arf tumor suppressor pathways have been linked to diverse cancer-relevant processes, including those governing the cellular responses to telomere dysfunction. In this study, we sought to provide direct genetic evidence of a role for the Ink4a/Arf tumor suppressor gene, encoding both p16 Ink4a and p19 Arf , in modulating the cellular and tissue phenotypes associated with telomere dysfunction by using the mTerc Ink4a/Arf mouse model. In contrast to the rescue associated with p53 deficiency, Ink4a/Arf deficiency did not attenuate the degenerative phenotypes elicited by telomere dysfunction in the late-generation mTerc؊/؊ mice. Furthermore, in contrast to accelerated cancer onset and increased epithelial cancers of late-generation mTerc؊/؊ p53 mutant mice, late-generation mTerc؊/؊ Ink4a/Arf mutant mice experienced a delayed tumor onset and maintained the lymphoma and sarcoma spectrum. Consistent with the negligible role of Ink4a/Arf in the telomere checkpoint response in vivo, late-generation mTerc؊/؊ Ink4a/Arf؊/؊ tissues show activated p53, and derivative tumor cell lines sustain frequent loss of p53 function, whereas all early generation mTerc Ink4a/Arf؊/؊ tumor cell lines remain intact for p53. In addition, the late-generation mTerc؊/؊ Ink4a/Arf؊/؊ tumors showed activation of the alternative lengthening of telomere mechanism, underscoring the need for adaptation to the presence of telomere dysfunction in the absence of p16 Ink4a and p19 Arf . These observations highlight the importance of genetic context in dictating whether telomere dysfunction promotes or suppresses age-related degenerative conditions as well as the rate of initiation and type of spontaneous cancers.telomere ͉ cancer aging ͉ checkpoint ͉ p53

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Section: Ink4amentioning

confidence: 88%

Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse

Khoo

Carrasco

Bosenberg

et al. 2007

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

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“…The increased tumor burden in these mice was significantly attenuated in those animals treated with an AKT inhibitor, suggesting that up-regulation of this pathway is associated with tumorigenesis [30]. Unlike the NF-λB pathway, the contribution of AKT signaling in histiocytic sarcoma has been previously reported [31]. In human specimens, immunohistochemistry revealed high levels of p-AKT expression in 9 of 10 histiocytic sarcoma samples [31].…”

Section: Discussionmentioning

confidence: 99%

NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

et al. 2016

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Histiocytic sarcoma is an uncommon malignancy in both humans and veterinary species. Research exploring the pathogenesis of this disease is scarce; thus, diagnostic and therapeutic options for patients are limited. Recent publications have suggested a role for the NLR, NLRX1, in acting as a tumor suppressor. Based on these prior findings, we hypothesized that NLRX1 would function to inhibit tumorigenesis and thus the development of histiocytic sarcoma. To test this, we utilized Nlrx1−/− mice and a model of urethane-induced tumorigenesis. Nlrx1−/− mice exposed to urethane developed splenic histiocytic sarcoma that was associated with significant up-regulation of the NF-λB signaling pathway. Additionally, development of these tumors was also significantly associated with the increased regulation of genes associated with AKT signaling, cell death and autophagy. Together, these data show that NLRX1 suppresses tumorigenesis and reveals new genetic pathways involved in the pathobiology of histiocytic sarcoma.

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“…Like FDCS, the pathogenesis in HS is unknown. Experimental models in mice have shown that loss of PTEN and INK4A / ARF results in histiocytic sarcoma [20]. Interestingly, genomic sequencing studies of Langerhans cell histiocytosis, which is a histiocytic neoplasm that arises from a specialised dendritic cell known as the Langerhans cell, has revealed mutually exclusive driving mutations of BRAF V600E and MAP2K1 mutations that implicate MAP kinase signalling cascade in the pathogenesis of this disorder [21–24].…”

Section: Discussionmentioning

confidence: 99%

Impact of surgery, radiation and systemic therapy on the outcomes of patients with dendritic cell and histiocytic sarcomas

Gounder

Desai

Kuk

et al. 2015

European Journal of Cancer

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Background Neoplasms of histiocytic and dendritic cell origin, including follicular dendritic cell sarcoma (FDCS), histiocytic sarcoma (HS) and interdigitating dendritic cell sarcoma (IDCS), are extremely rare, and data on their natural history and treatment outcomes are sparse. We evaluated the impact of surgery, radiation and systemic therapies on overall survival (OS). Methods We conducted a retrospective chart review of patients with FDCS, IDCS and HS treated at Memorial Sloan Kettering Cancer Center between 1995 and 2014. Results We identified 31, 15 and 7 patients with FDCS, HS and IDCS, respectively. Median age was 48.7, 42.3 and 58.8 years for FDCS, HS and IDCS, respectively. Only a slight disparity in gender distribution existed for FDCS and HS; however, IDCS predominantly affected males (6:1). The most common sites of presentation were abdomen and pelvis (42%), extremities (33%) and head and neck (57%) for FDCS, HS and IDCS, respectively. At diagnosis, 74%, 40% and 86% of patients presented with localised disease in FDCS, HS and IDCS, respectively. Patients with localised disease had significantly improved OS than those with metastatic disease in FDCS (P = 0.04) and IDCS (P = 0.014) but not in HS (P = 0.95). In FDCS and HS, adjuvant or neo-adjuvant therapy was not associated with improved OS compared with observation. In IDCS, surgery alone provided a 5-year overall survival rate of 71%. Conclusions Adjuvant or neo-adjuvant treatment in FDCS and HS did not affect OS. Patients with IDCS had an excellent outcome with surgery. In the metastatic setting, chemotherapy and small molecule inhibitors may provide benefit.

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The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans

Cited by 59 publications

References 49 publications

Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse

Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse

NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-λB signaling

Impact of surgery, radiation and systemic therapy on the outcomes of patients with dendritic cell and histiocytic sarcomas

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