Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells

Hiatt, Kelly; Ingram, David A.; Huddleston, Hannah; Spandau, Dan F.; Kapur, Reuben; Clapp, D. Wade

doi:10.1016/s0002-9440(10)63233-6

Cited by 24 publications

(15 citation statements)

References 46 publications

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“…[16][17][18] This notion is supported by the observations that various Nf1-deficient cells survive in the absence of trophic factors 19 and that enhanced survival of Nf1-deficient sensory neurons is dependent on Ras. [19][20][21] It is nevertheless possible that the proapoptotic action of neurofibromin is also exerted independently of Ras. The aim of the present study was to verify the existence of a proapoptotic action of neurofibromin, and -if confirmed -to determine the extent to which this putative action is dependent on Ras.…”

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confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio-and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1 À/À , Nf1 þ /À , and Nf1 þ / þ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.

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confidence: 99%

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

et al. 2006

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“…54 Loss of the NF1 GAP in hematopoietic cells, including but not limited to mast cells, increases the latency and potency of GTP-bound Ras and phosphorylated downstream effectors within the Raf-mitogen-activated protein (MAP)/extracellular signalrelated kinase (ERK) kinase (MEK)-ERK and phosphoinositide-3-kinase (PI3K)-Rac-p21-activated kinase (Pak)-P38 pathways. 36,57,59,[64][65][66][67][68][69][70] SCF-dependent c-kit signaling in the mast cell hinges specifically on K-ras pathways. 67 Immunoprecipitation experiments indicate that SCF:c-kit-activated Ras induces a cascade ultimately phosphorylating and activating p44/p42 (ERK1/2), p38, and AKT.…”

Section: Scf-and Nf1-dependent Mast Cell Biochemistrymentioning

confidence: 99%

Mast cells and the neurofibroma microenvironment

Staser¹,

Yang

Clapp

2010

Blood

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100

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Neurofibromatosis type 1 (NF1) is the most common genetic disorder with a predisposition to malignancy and affects 1 in 3500 persons worldwide. NF1 is caused by a mutation in the NF1 tumor suppressor gene that encodes the protein neurofibromin. Patients with NF1 have cutaneous, diffuse, and plexiform neurofibromas, tumors comprised primarily of Schwann cells, blood vessels, fibroblasts, and mast cells. Studies from human and murine models that closely recapitulate human plexiform neurofibroma formation indicate that tumorigenesis necessitates NF1 loss of heterozygosity in the Schwann cell. In addition, our most recent studies with bone marrow transplantation and pharmacologic experiments implicate haploinsufficiency of Nf1 (Nf1 ؉/؊ ) and ckit signaling in the hematopoietic system as required and sufficient for tumor progression. Here, we review recent studies implicating the hematopoietic system in plexiform neurofibroma genesis, delineate the physiology of stem cell factordependent hematopoietic cells and their contribution to the neurofibroma microenvironment, and highlight the application of this research toward the first successful, targeted medical treatment of a patient with a nonresectable and debilitating neurofibroma. Finally, we emphasize the importance of the tumor microenvironment hypothesis, asserting that tumorigenic cells in the neurofibroma do not arise and grow in isolation. (Blood. 2010; 116(2):157-164) IntroductionAlthough several reports characterized neurofibromatosis type 1 (NF1) or NF1-like syndromes as early as the 18th century, [1][2][3] Friedrich von Recklinghausen did not publish his seminal, detailed case reports until 1882. 4 Von Recklinghausen observed that neurofibromas contain elements of both neuronal and fibroblastic tissue. In 1911, H. Greggio reported his observation that mast cells infiltrate the neurofibroma. 5,6 Vincent Riccardi later postulated a pivotal role for mast cells and melanocytes in NF1 pruritus, pigmentation defects, and, potentially, neurofibroma formation. 7 Today, NF1 is recognized as a common and fully penetrant genetic disease that shows variable expressivity. 6-9 The disease is transmitted in an autosomal dominant fashion as a mutation in NF1, a tumor suppressor gene encoding the protein neurofibromin. Neurofibromin functions as a p21 ras (Ras) guanosine triphosphatase (GTP)-activating protein (GAP), accelerating the hydrolysis of Ras-GTP thousands of fold and functioning at least in part to negatively regulate multiple Ras-dependent cellular signaling pathways. 6,[10][11][12][13][14][15][16] Mutations of NF1 predispose patients to variable neuronal, hematopoietic, and skeletal disorders, including myeloid leukemia, kyphoscoliosis, long bone pseudoarthrosis, and cutaneous, subcutaneous, and diffuse plexiform neurofibromas. 6,17 Neurofibromas are pathognomonic for the disease. Cutaneous neurofibromas arise from small peripheral nerves during adolescence or adulthood and are observed in greater than 95% of patients with NF1 (Figure 1 left). 18 Plexiform neu...

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“…In addition to promoting growth at limiting concentrations of growth factors that may be particularly relevant at physiologic concentrations, Nf1 -/-myeloid progenitors (14) and Nf1 +/-mast cells (13) have increased survival associated with an increase in PI3K activity. To examine whether this phenotype is present in Nf1 +/-osteoclasts, purified osteoclasts were cultured in M-CSF in the absence of serum, and apoptosis was determined sequentially over 24 hours using annexin V staining.…”

Section: Nf1 +/-Mice Have Increased Numbers Of Osteoclast Progenitorsmentioning

confidence: 99%

“…Further, mice transplanted with Nf1 -/-fetal liver hematopoietic stem cells uniformly develop a myeloid leukemia (10,11) that is highly reminiscent of the juvenile myelomonocytic leukemia observed in children with NF1 (12). Recent studies in Nf1 +/-mast cells (7,8,13) and in Nf1 -/-myeloid progenitors (14) link increased activation of the p21 ras /PI3K signaling pathway to multiple neurofibromin-deficient mast cell and myeloid progenitor phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1–haploinsufficient osteoclast functions

Yang¹,

Chen²,

Robling³

et al. 2006

J. Clin. Invest.

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Individuals with neurofibromatosis type 1 (NF1) have a high incidence of osteoporosis and osteopenia. However, understanding of the cellular and molecular basis of these sequelae is incomplete. Osteoclasts are specialized myeloid cells that are the principal bone-resorbing cells of the skeleton. We found that Nf1 +/-mice contain elevated numbers of multinucleated osteoclasts. Both osteoclasts and osteoclast progenitors from Nf1 +/-mice were hyperresponsive to limiting concentrations of M-CSF and receptor activator of NF-κB ligand (RANKL) levels. M-CSF-stimulated p21 ras -GTP and Akt phosphorylation was elevated in Nf1 +/-osteoclasts associated with gains of function in survival, proliferation, migration, adhesion, and lytic activity. These gains of function are associated with more severe bone loss following ovariectomy as compared with that in syngeneic WT mice. Intercrossing Nf1 +/-mice and mice deficient in class 1 A PI3K (p85α) restored elevated PI3K activity and Nf1 +/-osteoclast functions to WT levels. Furthermore, in vitro-differentiated osteoclasts from NF1 patients also displayed elevated Ras/PI3K activity and increased lytic activity analogous to those in murine Nf1 +/-osteoclasts. Collectively, our results identify a what we believe to be a novel cellular and biochemical NF1-haploinsufficient phenotype in osteoclasts that has potential implications for the pathogenesis of NF1 bone disease. IntroductionNeurofibromatosis type 1 (NF1) is a common, pandemic genetic disorder that is characterized by a range of both malignant and nonmalignant manifestations and is caused by mutations in the NF1 gene. Neurofibromin, the protein encoded by NF1, functions as a GTPase-activating protein (GAP) for Ras. Though loss of both alleles of NF1 in tumorigenic cells is consistent with NF1 being a tumor suppressor gene, recent genetic evidence in murine models has indicated that nullizygous loss of Nf1 in the tumorigenic cells of plexiform neurofibromas (1) and optic gliomas (2) is necessary but not sufficient for tumor progression, though tumors occur with high penetrance when lineages of the tumor microenvironment are haploinsufficient at Nf1. These in vivo data provide evidence that haploinsufficiency of Nf1 in at least a subset of lineages has a role in the malignant manifestations of NF1 and also suggest a potential role for haploinsufficiency of Nf1 (NF1) in the nonmalignant pathogenesis of NF1.Three recent reports, including a controlled trial using WHO criteria for osteoporosis and osteopenia, have provided evidence that NF1 patients have a significantly higher incidence of osteoporosis and osteopenia (3-5). Bone homeostasis is maintained by balancing skeletal matrix formation and resorption. Osteoclasts are specialized cells derived from the myeloid monocyte/macro-

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Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells

Cited by 24 publications

References 46 publications

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

The tumor suppressor neurofibromin confers sensitivity to apoptosis by Ras-dependent and Ras-independent pathways

Mast cells and the neurofibroma microenvironment

Hyperactivation of p21ras and PI3K cooperate to alter murine and human neurofibromatosis type 1–haploinsufficient osteoclast functions

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