Original Article
Homozygous Inactivation of the NF1 Gene in Bone Marrow Cells from Children with Neurofibromatosis Type 1 and Malignant Myeloid Disorders
N Engl J Med 1997; 336:1713-1720June 12, 1997
- Abstract
Background
The risk of malignant myeloid disorders in young children with neurofibromatosis type 1 is 200 to 500 times the normal risk. The gene for neurofibromatosis type 1 (NF1) encodes neurofibromin, a protein that negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells, but inactivation of both NF1 alleles has not been demonstrated in leukemic cells from patients with neurofibromatosis type 1.
Methods
Using an in vitro transcription and translation system, we screened bone marrow samples from 18 children with neurofibromatosis type 1 and myeloid disorders for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from their affected parents, in cases of familial neurofibromatosis type 1.
Results
Specimens from 9 of the 18 children contained abnormal peptide fragments, and truncating mutations of the NF1 gene were found in specimens from 8 of these children. The normal NF1 allele was absent in bone marrow samples from five of the eight children. We detected the same mutation in DNA from the affected parent of each child with familial neurofibromatosis type 1.
Conclusions
Both alleles of the NF1 gene are inactivated in leukemic cells in some patients with neurofibromatosis type 1. NF1 appears to function as a tumor-suppressor gene in immature myeloid cells.
Media in This Article
Figure 3
Homozygous Inactivation of the NF1 Gene in a Child with Leukemia.Figure 1
Use of in Vitro Transcription and Translation (IVTT) to Detect NF1 Mutations.Article Activity
- Article
Neurofibromatosis type 1 is an autosomal dominant disorder with an incidence of approximately 1 in 3500 people.1 Patients with the disease have a predisposition to particular benign and malignant neoplasms, which arise primarily from cells of neural-crest origin. These tumors include neurofibromas, neurofibrosarcomas, optic gliomas, and pheochromocytomas.1 In young children with neurofibromatosis type 1, the risk of malignant myeloid disorders, particularly juvenile myelomonocytic leukemia (formerly known as juvenile chronic myelogenous leukemia) and the monosomy 7 syndrome, a childhood variant of myelodysplasia, is 200 to 500 times the normal risk.2-5 These diseases are more common in boys than in girls, and hepatosplenomegaly, leukocytosis, the absence of the Philadelphia chromosome, and a poor prognosis are characteristic.6,7 Adults with neurofibromatosis type 1 do not appear to have an increased risk of leukemia.
The RAS family of proto-oncogenes encodes proteins that regulate cellular proliferation and differentiation by cycling between an active guanosine triphosphate (GTP)–bound state and an inactive guanosine diphosphate (GDP)–bound state.8,9 Neurofibromin, the 327-kd protein encoded by the gene for neurofibromatosis type 1 (NF1), contains a domain with considerable sequence homology with both yeast and mammalian GTPase-activating proteins.10,11 When this GTPase-activating domain of neurofibromin binds Ras protein, it accelerates the conversion of Ras–GTP to Ras–GDP by increasing intrinsic Ras–GTPase activity.12 Activating point mutations of RAS proto-oncogenes are among the most common molecular alterations in human cancer cells and are frequent in myeloid leukemias.13,14
The detection of activating RAS mutations in many human tumors, biochemical evidence that neurofibromin negatively regulates Ras–GTP, and the increased risk of cancer in patients with neurofibromatosis type 1 all suggest that the NF1 gene functions as a tumor-suppressor gene. As first proposed by Knudson, tumorigenesis requires inactivation of both alleles of a tumor-suppressor gene: the first event occurs in the germ line, the second in a somatic cell.15 Thus, notwithstanding the inheritance of the clinical syndrome of neurofibromatosis type 1 in an autosomal dominant fashion, the Knudson model predicts a somatic inactivation of the remaining normal NF1 allele in the cancers that develop in patients with neurofibromatosis type 1. According to this model, the NF1 gene, like other tumor-suppressor genes, should behave in a recessive manner in cancer cells. Inactivation of the normal copy of a tumor-suppressor gene may occur by deletion, resulting in loss of constitutional heterozygosity, or by more subtle changes, such as point mutations. Loss of heterozygosity at NF1 is frequent in neurofibrosarcomas,16-18 pheochromocytomas,19 and neurofibromas20 from patients with neurofibromatosis type 1. We detected loss of heterozygosity at the NF1 gene in leukemic cells from 10 of 22 children with neurofibromatosis type 1 and myeloid disorders, and we confirmed that the retained allele was inherited from the affected parent in familial cases.21,22 Experiments with purified populations of bone marrow cells have shown that loss of heterozygosity is restricted to immature myeloid cells in most patients and generally does not affect lymphoid precursors (or Epstein–Barr virus [EBV]–transformed B cells), suggesting that lymphoid precursors are not part of the malignant clone.22 The loss of heterozygosity at the NF1 gene in neural-crest–derived tumors and leukemias in some patients with neurofibromatosis type 1 indicates that the NF1 gene functions as a tumor-suppressor gene, but a rigorous proof of this hypothesis must demonstrate inactivation of both NF1 alleles in primary tumors. To date, deletions of both NF1 alleles have been reported in only two patients with neurofibromatosis type 1: one with a neurofibrosarcoma23 and one with a dermal neurofibroma.24
The detection of mutations in the NF1 gene is technically challenging because the gene spans 59 exons and encodes a 13-kb messenger RNA (mRNA).25 Conventional techniques, such as single-stranded conformation polymorphism analysis and Southern blotting, have detected mutations in fewer than 20 percent of patients who meet generally accepted diagnostic criteria for neurofibromatosis type 1.26 Approximately 80 percent of the known NF1 mutations are nonsense mutations or small insertions or deletions that cause premature termination of translation.26-28 A coupled in vitro transcription and translation assay (IVTT) has been used successfully to screen for mutations of other tumor-suppressor genes, such as APC 29 and BRCA1, 30 in which nonsense or frame-shift mutations are frequent. Heim et al.28 adapted this technique to screen for NF1 mutations and detected mutations in 67 percent of an unselected group of patients. In this study, we used IVTT to test specimens from 18 children with neurofibromatosis type 1 and myeloid disorders for NF1 mutations.
Methods
We studied all children with neurofibromatosis type 1 and myeloid disorders who were referred to our laboratory over a seven-year period and from whom there was enough material for RNA extraction. Fresh or frozen bone marrow samples were available from 13 patients, frozen splenic tissue from 1, and EBV-transformed cell lines from 6 (Table 1Table 1
Characteristics of 18 Children with Neurofibromatosis Type 1 and Malignant Myeloid Disorders.). Most of these samples had been studied previously for loss of heterozygosity at the NF1 gene.21,22,31 We used polymorphic tandem-repeat markers, as described in detail previously, to detect loss of heterozygosity at the NF1 gene.21,22,32 Parental DNA was available to confirm the mutations by direct sequencing in most cases of familial neurofibromatosis type 1. The experimental procedures were approved by the institutional review board of the University of California at San Francisco, and informed consent was obtained from the families who participated in the study.Total cellular RNA was extracted from bone marrow mononuclear cells or EBV-transformed lymphoblastoid cells by a single-step method of RNA isolation with the use of a monophasic solution of phenol and guanidium isothiocyanate (Trizol reagent, GIBCO BRL). We used the general experimental conditions and oligonucleotide primers as described elsewhere for the IVTT assay.28 IVTT analysis detects nonsense or frame-shift mutations by transcribing amplified complementary DNA (cDNA) into mRNA and translating mRNA into protein in a single reaction (Figure 1AFigure 1
Use of in Vitro Transcription and Translation (IVTT) to Detect NF1 Mutations.). Truncating mutations are represented by radiolabeled peptides that are smaller than those derived from the normal gene product on gel electrophoresis. First-strand cDNA was synthesized from total cellular RNA with the use of random hexamers. Reverse-transcriptase–polymerase-chain-reaction (RT-PCR) amplification was performed in duplicate with five oligonucleotide primer pairs that amplify the entire NF1 protein-coding sequence (exons 1 through 49) in five overlapping segments of approximately 2 kb each.28 The forward primer contained a T7 RNA polymerase promoter sequence as well as a translation-initiation site. A 2-μl aliquot of PCR product and 10 μCi of 35S-labeled methionine were added to a coupled transcription–translation system containing rabbit reticulocyte lysate (Promega) and incubated at 30°C for one hour. The resulting peptides were resolved by electrophoresis on a 12.5 percent sodium dodecyl sulfate–polyacrylamide gel and visualized by autoradiography.RT-PCR products that gave rise to truncated proteins were cloned with the use of the CloneAmp vector system (GIBCO BRL), as described elsewhere.33 Plasmid DNA was extracted from individual transformed colonies after overnight culture and used as a template for a second round of IVTT. Plasmid-derived IVTT polypeptides were judged to comigrate with either the normal or the truncated protein by gel electrophoresis, and only cDNA prepared from colonies giving rise to truncated protein were sequenced.34 Direct sequencing of cloned cDNA was performed by automated methods with the use of either fluorescein-labeled dideoxy terminators (Applied Biosystems) or Sequenase, version 2.0 (U.S. Biochemical). Mutations were confirmed in genomic DNA derived from leukemic cells by amplifying the relevant exon with the use of primers described elsewhere35 and performing cloning and sequencing reactions as described above. In cases of familial neurofibromatosis type 1, parental genomic DNA was sequenced to determine whether mutations detected in the leukemic clone were the cause of the disorder.
Results
The clinical characteristics of the 18 patients are shown in Table 1. The study group included 12 boys and 6 girls, with a median age of 18 months at the onset of the hematologic disease. Seven children had juvenile myelomonocytic leukemia, two had the monosomy 7 syndrome, two had chronic myelomonocytic leukemia, and two had an atypical myelodysplasia that did not conform to a specific diagnostic category. In four patients myelodysplasia with monosomy 7 developed after cytotoxic therapy for another cancer.31 Ten cases of neurofibromatosis type 1 were familial and eight were sporadic.
Half the bone marrow samples studied showed loss of heterozygosity at the NF1 gene. All five segments of the gene were amplified successfully by RT-PCR in each sample. In nine cases, one or more abnormal peptide bands were detected in one of the five NF1 segments. Representative data are shown in Figure 1B. To characterize each NF1 mutation, RT-PCR products that gave rise to truncated proteins were cloned and subjected to a second round of IVTT. Figure 2AFigure 2
Use of in Vitro Transcription and Translation (IVTT) to Screen Transformed Colonies for Plasmid DNA with Mutant NF1 Sequences. summarizes this strategy, and Figure 2B shows data from two patients. Only clones that yielded an abnormal peptide by second-stage IVTT were sequenced.Truncating mutations of the NF1 gene were confirmed in cDNA and genomic DNA from eight children (Table 2Table 2
NF1 Mutations in Eight of the Children with Neurofibromatosis Type 1 and Malignant Myeloid Disease.). Of the eight fully characterized abnormalities, two were nonsense and six were frame-shift mutations resulting in early termination. In one patient, sequence analysis of cDNA extracted from two colonies that gave rise to abnormal polypeptides on second-stage IVTT showed only the absence of exon 23a, an exon known to be alternatively spliced. This isoform, known as type II neurofibromin, has a GTPase-activating function and is therefore unlikely to be involved in leukemogenesis.36 In Patients 2, 12, and 17, direct sequencing of cloned cDNA revealed aberrant splicing, with a consequent shift in the reading frame in Patients 2 and 12. Genomic DNA from Patient 2 showed an alteration (6756 + 3 A→G; 6756 + 6 del TCG) in the splice-donor consensus sequence flanking the 3' end of exon 36. This abnormality was also present in genomic DNA from the patient's affected mother and was assumed to be the cause of the exon skipping, since exon 36 is not known to be alternatively spliced. The genomic DNA sequences from Patient 12 and his mother showed an abnormal splice-acceptor sequence upstream of exon 11 (1642 - 8 A→G), which appears to create a cryptic splice site resulting in an aberrant cDNA sequence. The mutation found in Patient 17 (5749 + 332 G→A) created a cryptic splice-donor site in intron 30, allowing the splicing of 180 nucleotides of intronic sequence between exons 30 and 31. This abnormally spliced fragment contained an in-frame stop codon.Specimens of leukemic bone marrow from five of the eight patients with truncating NF1 mutations showed loss of heterozygosity at the NF1 gene. Two of these eight children had sporadic neurofibromatosis type 1 (Table 1). In all six patients with the familial disorder, genomic DNA from the affected parent had the same mutation as DNA from the child. For example, Patient 5 inherited the disorder from his father, and the normal maternal NF1 allele was lost from his leukemic cells. A four-nucleotide deletion was identified in exon 28 in both father and son (Figure 3Figure 3
Homozygous Inactivation of the NF1 Gene in a Child with Leukemia.). The mutations in the two children with sporadic cases (Patients 4 and 10) have been documented previously in three unrelated patients with neurofibromatosis type 1,28 none of whom had leukemia.We prepared lysates from three EBV-transformed cell lines that had germ-line NF1 mutations (derived from Patients 4, 9, and 11) and performed immunoprecipitation followed by Western blotting with the use of an antibody to the N-terminus of neurofibromin. These experiments showed only normal-size neurofibromin (data not shown). Failure to detect the truncated peptides indicates that they are probably unstable in vivo and are therefore unlikely to function by means of a dominant negative mechanism.
Discussion
We found mutations that resulted in truncated neurofibromin peptides in 8 of 18 children with neurofibromatosis type 1 and malignant myeloid disorders. In all six cases of familial neurofibromatosis type 1, the same mutation was present in DNA from the affected parent and bone marrow or EBV-transformed B cells from the child. This finding shows that the mutations in the leukemic specimens were the cause of neurofibromatosis type 1 in these families rather than somatic changes that arose in the abnormal clones. Furthermore, we demonstrated loss of the normal NF1 allele in leukemic specimens from five patients with truncating mutations (including the child whose findings are shown in Figure 3), and in vivo studies showed no expression of the abnormal proteins.
These data indicate that leukemogenesis in some children with neurofibromatosis type 1 entails the inactivation of both NF1 alleles. Loss of functional neurofibromin may be a general feature of the myeloid disorders that arise in children with this disorder. However, we did not identify NF1 mutations in all the leukemic specimens, perhaps because the IVTT method does not detect inactivating missense mutations or truncating mutations that render the NF1 mRNA highly unstable. Also, we did not examine the promoter region of NF1 for mutations that may reduce mRNA levels, nor did we investigate the 3' untranslated region of the gene, where there may be alterations that destabilize the protein. Our data are consistent both with experiments showing that loss of heterozygosity at the NF1 gene is common in a variety of tumors that develop in patients with neurofibromatosis type 119-22 and with reports of deletions encompassing both NF1 alleles in a patient with a neurofibrosarcoma23 and a patient with a dermal neurofibroma.24
Genetic and biochemical data support the hypothesis that neurofibromin restrains the growth of immature myeloid cells by negatively regulating Ras proteins. In a study of children with myelodysplasia, RAS mutations were found in bone marrow cells from 21 percent of 55 children without neurofibromatosis type 1, but no RAS alterations were detected in leukemic cells from 16 children with the disorder.33 A moderate but consistent elevation in the percentage of GTP-bound Ras proteins and a significant reduction in neurofibromin-related GTPase-activating–protein activity have been reported in leukemic cells from children with neurofibromatosis type 1.37 Loss of heterozygosity at the NF1 gene has been demonstrated in a number of neural-crest tumors,16-20 but activating RAS mutations are rare in these cancers, unlike myeloid leukemias. Neurofibrosarcoma cell lines derived from patients with neurofibromatosis type 1 show a marked elevation in the percentage of Ras–GTP and a reduction in GTPase-activating–protein activity38,39; however, neuroblastoma and melanoma cell lines frequently lack neurofibromin yet maintain normal levels of Ras–GTP.40,41 These data suggest that neurofibromin may regulate the growth of some cells of neural-crest lineage by a mechanism that is independent of Ras protein. In contrast, the evidence strongly implicates deregulation of the Ras pathway in the pathogenesis of myeloid leukemias associated with neurofibromatosis type 1.
Correlations between particular mutations (genotype) and clinical features (phenotype) have been observed in a number of dominantly inherited cancers. Low-penetrance retinoblastoma has been documented in at least three families.42,43 Uncharacteristically, these patients had promoter mutations or in-frame deletions of the retinoblastoma gene (RB), so perhaps these alleles make some functional RB protein, which could account for the milder disease. Seven percent of patients with von Hippel–Lindau disease have pheochromocytomas, and these patients tend to have missense mutations rather than the more common truncating mutations of the gene for the disease.44,45 Our results do not support the hypothesis of a correlation between the genotype in neurofibromatosis type 1 and childhood myelodysplasia. None of the mutated alleles we found are specific for leukemia, and we found no evidence of a predisposition to cancer in the families of our patients with neurofibromatosis type 1. Variable expression of the benign features of the disorder within families is well documented and may be determined by the genotype at modifying loci.46 In children with neurofibromatosis type 1, inactivation of the normal NF1 allele appears to have a role in the development of leukemia, along with such epigenetic factors as male sex, maternal transmission, and loss of chromosome 7 in many patients.4,22
IVTT has been successfully used to detect mutations in two other large tumor-suppressor genes.29,30 The specificity of this technique is high, but there was one false positive result among our 18 patients, which was due to an exon known to be alternatively spliced. IVTT may therefore best be regarded as a screening procedure, with DNA sequencing performed to confirm a mutation when a truncated peptide is found.
A murine model of neurofibromatosis type 1 is also characterized by a predisposition to cancer, but without the pigmentation defects and benign neurofibromas of the disease.47 Embryos homozygous for a disrupted Nf1 allele die in utero from cardiac defects.47,48 From 15 months of age, heterozygous mice have a predisposition to myeloid leukemias and other tumors, most of which are characterized by deletion of the wild-type Nf1 allele.47 Hematopoietic cells from the livers of embryos that are homozygous for Nf1 mutations can reconstitute hematopoiesis in lethally irradiated recipient animals, in whom a disorder resembling juvenile myelomonocytic leukemia subsequently develops49 (and unpublished data). The homozygous inactivation of the NF1 gene in human leukemic cells suggests that this murine model will prove useful for testing novel anti–Ras-protein drugs such as farnesyl transferase inhibitors.50,51 The development of treatments that target the underlying biochemical abnormalities in tumor cells may improve the outcome for patients with neoplasms associated with neurofibromatosis type 1 and other cancers characterized by hyperactive Ras protein.
Supported in part by grants from the National Institutes of Health (RR01271-13S1 and CA72614), the American Cancer Society (JFRA-471), the U.S. Army Medical Research and Development Command (DAMD17-93-J-3075), the Concern 2 Foundation, and the Frank A. Campini Foundation. Dr. Side was the recipient of fellowships from the Sir Halley Stewart Trust and the Lady Tata Memorial Trust.
We are indebted to Dr. David Viskochil for providing us with the NF1 intronic sequence and advice regarding primer sequences, to Dr. Nancy Ratner for antibodies to the N-terminus of neurofibromin, to Dr. Karen Stephens for the Epstein–Barr virus line derived from Patient 4, to the families who participated in the study, to the physicians from around the world for providing specimens and clinical data, and to the Children's Cancer Group for their collaboration.
Source Information
From the Department of Pediatrics, University of California, San Francisco (L.S., B.T., E.C., P.T., K.S.); and Roche Biomedical Laboratories, Research Triangle Park, N.C. (M.C., M.L.).
Address reprint requests to Dr. Shannon at Box 0519, University of California, 513 Parnassus Ave., San Francisco, CA 94143-0519.
- References
References
1
Riccardi VM, Eichner JE. Neurofibromatosis: phenotype, natural history, and pathogenesis. Baltimore: Johns Hopkins University Press, 1986.
2
Castro-Malaspina H ,Schaison G ,Passe S , et al. Subacute and chronic myelomonocytic leukemia in children (juvenile CML): clinical and hematologic observations, and identification of prognostic factors. Cancer 1984;54:675-686
CrossRef | Web of Science | Medline3
Passmore SJ ,Hann IM ,Stiller CA , et al. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 1995;85:1742-1750
Web of Science | Medline4
Shannon KM ,Watterson J ,Johnson P , et al. Monosomy 7 myeloproliferative disease in children with neurofibromatosis, type 1: epidemiology and molecular analysis. Blood 1992;79:1311-1318
Web of Science | Medline5
Stiller CA ,Chessells JM ,Fitchett M . Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 1994;70:969-972
CrossRef | Web of Science | Medline6
Emanuel PD ,Shannon KM ,Castleberry RP . Juvenile myelomonocytic leukemia: molecular understanding and prospects for therapy. Mol Med Today 1996;2:468-475
CrossRef | Medline7
Gadner H ,Haas OA . Experience in pediatric myelodysplastic syndromes. Hematol Oncol Clin North Am 1992;6:655-672
Web of Science | Medline8
Bourne HR ,Sanders DA ,McCormick F . The GTPase superfamily: a conserved switch for diverse cell functions. Nature 1990;348:125-132
CrossRef | Web of Science | Medline9
Hall A . The cellular functions of small GTP-binding proteins. Science 1990;249:635-640
CrossRef | Web of Science | Medline10
Ballester R ,Marchuk D ,Boguski M , et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 1990;63:851-859
CrossRef | Web of Science | Medline11
Xu GF ,O'Connell P ,Viskochil D , et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 1990;62:599-608
CrossRef | Web of Science | Medline12
Boguski M ,McCormick F . Proteins regulating Ras and its relatives. Nature 1993;366:643-654
CrossRef | Web of Science | Medline13
Bos JL . ras Oncogenes in human cancer: a review. Cancer Res 1989;49:4682-4689[Erratum, Cancer Res 1990;50:1352.]
Web of Science | Medline14
Rodenhuis S . ras And human tumors. Semin Cancer Biol 1992;3:241-247
Medline15
Weinberg RA . Tumor suppressor genes. Science 1991;254:1138-1146
CrossRef | Web of Science | Medline16
Skuse GR ,Kosciolek BA ,Rowley PT . Molecular genetic analysis of tumors in von Recklinghausen neurofibromatosis: loss of heterozygosity for chromosome 17. Genes Chromosomes Cancer 1989;1:36-41
CrossRef | Web of Science | Medline17
Glover TW ,Stein CK ,Legius E ,Andersen LB ,Brereton A ,Johnson S . Molecular and cytogenetic analysis of tumors in von Recklinghausen neurofibromatosis. Genes Chromosomes Cancer 1991;3:62-70
CrossRef | Web of Science | Medline18
Menon AG ,Anderson KM ,Riccardi VM , et al. Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A 1990;87:5435-5439
CrossRef | Web of Science | Medline19
Xu W ,Mulligan L ,Ponder MA , et al. Loss of NF1 alleles in phaeochromocytomas from patients with type 1 neurofibromatosis. Genes Chromosomes Cancer 1992;4:337-342
CrossRef | Web of Science | Medline20
Colman SD ,Williams CA ,Wallace MR . Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nat Genet 1995;11:90-92
CrossRef | Web of Science | Medline21
Shannon KM ,O'Connell P ,Martin GA , et al. Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 1994;330:597-601
Full Text | Web of Science | Medline22
Miles DK ,Freedman MH ,Stephens K , et al. Patterns of hematopoietic lineage involvement in children with neurofibromatosis type 1 and malignant myeloid disorders. Blood 1996;88:4314-4320
Web of Science | Medline23
Legius E ,Marchuk DA ,Collins FS ,Glover TW . Somatic deletion of the neurofibromatosis type 1 gene in a neurofibrosarcoma supports a tumour suppressor gene hypothesis. Nat Genet 1993;3:122-126
CrossRef | Web of Science | Medline24
Sawada S ,Florell S ,Purandare S ,Ota M ,Stephens K ,Viskochil D . Identification of NF1 mutations in both alleles of a dermal neurofibroma. Nat Genet 1996;14:110-112
CrossRef | Web of Science | Medline25
Li Y ,O'Connell P ,Breidenbach HH , et al. Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics 1995;25:9-18
CrossRef | Web of Science | Medline26
Upadhyaya M ,Shaw DJ ,Harper PS . Molecular basis of neurofibromatosis type 1 (NF1): mutation analysis and polymorphisms in the NF1 gene. Hum Mutat 1994;4:83-101
CrossRef | Web of Science | Medline27
Heim RA ,Silverman LM ,Farber RA ,Kam-Morgan LN ,Luce MC . Screening for truncated NF1 proteins. Nat Genet 1994;8:218-219
CrossRef | Web of Science | Medline28
Heim RA ,Kam-Morgan LN ,Binnie CG , et al. Distribution of 13 truncating mutations in the neurofibromatosis 1 gene. Hum Mol Genet 1995;4:975-981
CrossRef | Web of Science | Medline29
Powell SM ,Petersen GM ,Krush AJ , et al. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993;329:1982-1987
Full Text | Web of Science | Medline30
FitzGerald MG ,MacDonald DJ ,Krainer M , et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996;334:143-149
Full Text | Web of Science | Medline31
Maris JM ,Wiersma SR ,Mahgoub N , et al. Monosomy 7 myelodysplastic syndrome and other second malignant neoplasms in children with neurofibromatosis type 1. Cancer 1997;79:1438-1446
CrossRef | Web of Science | Medline32
Jensen S ,Paderanga DC ,Chen P , et al. Molecular analysis at the NF1 locus in astrocytic brain tumors. Cancer 1995;76:674-677
CrossRef | Web of Science | Medline33
Kalra R ,Paderanga DC ,Olson K ,Shannon KM . Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras. Blood 1994;84:3435-3439
Web of Science | Medline34
Binnie CG ,Kam-Morgan LNW ,Cayouette MC ,Marra G ,Boland CR ,Luce MC . Rapid identification of RT-PCR clones containing translation-terminating mutations. Mutat Res 1997;388:21-26
Web of Science | Medline35
Purandare SM ,Huntsman Breidenbach H ,Li Y , et al. Identification of neurofibromatosis 1 (NF1) homologous loci by direct sequencing, fluorescence in situ hybridization, and PCR amplification of somatic cell hybrids. Genomics 1995;30:476-485
CrossRef | Web of Science | Medline36
Andersen LB ,Ballester R ,Marchuk DA , et al. A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol 1993;13:487-495
Web of Science | Medline37
Bollag G ,Clapp DW ,Shih S , et al. Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 1996;12:144-148
CrossRef | Web of Science | Medline38
Basu TN ,Gutmann DH ,Fletcher JA ,Glover TW ,Collins FS ,Downward J . Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 1992;356:713-715
CrossRef | Web of Science | Medline39
DeClue JE ,Papageorge AG ,Fletcher JA , et al. Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 1992;69:265-273
CrossRef | Web of Science | Medline40
The I ,Murthy AE ,Hannigan GE , et al. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat Genet 1993;3:62-66
CrossRef | Web of Science | Medline41
Johnson MR ,Look AT ,DeClue JE ,Valentine MB ,Lowy DR . Inactivation of the NF1 gene in human melanoma and neuroblastoma cell lines without impaired regulation of GTP.Ras. Proc Natl Acad Sci U S A 1993;90:5539-5543
CrossRef | Web of Science | Medline42
Sakai T ,Ohtani N ,McGee T ,Robbins PD ,Dryja TP . Oncogenic germ-line mutations in Sp1 and ATF sites in the human retinoblastoma gene. Nature 1991;353:83-86
CrossRef | Web of Science | Medline43
Dryja TP ,Rapaport J ,McGee TL ,Nork TM ,Schwartz TL . Molecular etiology of low-penetrance retinoblastoma in two pedigrees. Am J Hum Genet 1993;52:1122-1128
Web of Science | Medline44
Chen F ,Kishida T ,Yao M , et al. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 1995;5:66-75
CrossRef | Web of Science | Medline45
Crossey PA ,Richards FM ,Foster K , et al. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor geneand correlation with disease phenotype. Hum Mol Genet 1994;3:1303-1308
CrossRef | Web of Science | Medline46
Easton DF ,Ponder MA ,Huson SM ,Ponder BA . An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet 1993;53:305-313
Web of Science | Medline47
Jacks T ,Shih TS ,Schmitt EM ,Bronson RT ,Bernards A ,Weinberg RA . Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat Genet 1994;7:353-361
CrossRef | Web of Science | Medline48
Brannan CI ,Perkins AS ,Vogel KS , et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev 1994;8:1019-1029[Erratum, Genes Dev 1994;8:2792.]
CrossRef | Web of Science | Medline49
Largaespada DA ,Brannan CI ,Jenkins NA ,Copeland NG . Nf1 deficiency causes Ras-mediated granulocyte/macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia. Nat Genet 1996;12:137-143
CrossRef | Web of Science | Medline50
Gibbs JB ,Oliff A ,Kohl NE . Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 1994;77:175-178
CrossRef | Web of Science | Medline51
Kohl NE ,Omer CA ,Conner MW , et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995;1:792-797
CrossRef | Web of Science | Medline
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Marco Tartaglia, Bruce D. Gelb. (2010) Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Annals of the New York Academy of Sciences 1214:1, 99-121
CrossRef5
Karl Staser, Feng-Chun Yang, David W Clapp. (2010) Plexiform neurofibroma genesis: questions of Nf1 gene dose and hyperactive mast cells. Current Opinion in Hematology 17:4, 287-293
CrossRef6
Marie-Theres Girtler, Tobias De Zordo, Cesare Romagnoli. (2010) Sonographic findings in a patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor. Journal of Clinical Ultrasound 38:5, 274-278
CrossRef7
C. Batz, H. Hasle, E. Bergstrasser, M. M. van den Heuvel-Eibrink, M. Zecca, C. M. Niemeyer, C. Flotho, . (2010) Does SPRED1 contribute to leukemogenesis in juvenile myelomonocytic leukemia (JMML)?. Blood 115:12, 2557-2558
CrossRef8
Elaine Cham, Dawn Siegel, Beth S. Ruben. (2010) Cutaneous Xanthogranulomas, Hepatosplenomegaly, Anemia, and Thrombocytopenia as Presenting Signs of Juvenile Myelomonocytic Leukemia. American Journal of Clinical Dermatology 11:1, 67-71
CrossRef9
Irene Bottillo, Isabella Torrente, Valentina Lanari, Valentina Pinna, Sandra Giustini, Luigina Divona, Alessandro De Luca, Bruno Dallapiccola. (2010) Germline mosaicism in neurofibromatosis type 1 due to a paternally derived multi-exon deletion. American Journal of Medical Genetics Part An/a-n/a
CrossRef10
Matthew J Walter, Timothy A Graubert, John F DiPersio, Elaine R Mardis, Richard K Wilson, Timothy J Ley. (2009) Next-generation sequencing of cancer genomes: back to the future. Personalized Medicine 6:6, 653-662
CrossRef11
Takashi Matozaki, Yoji Murata, Yasuyuki Saito, Hideki Okazawa, Hiroshi Ohnishi. (2009) Protein tyrosine phosphatase SHP-2: A proto-oncogene product that promotes Ras activation. Cancer Science 100:10, 1786-1793
CrossRef12
Jennifer O. Lauchle, Doris Kim, Doan T. Le, Keiko Akagi, Michael Crone, Kimberly Krisman, Kegan Warner, Jeannette M. Bonifas, Qing Li, Kristen M. Coakley, Ernesto Diaz-Flores, Matthew Gorman, Sally Przybranowski, Mary Tran, Scott C. Kogan, Jeroen P. Roose, Neal G. Copeland, Nancy A. Jenkins, Luis Parada, Linda Wolff, Judith Sebolt-Leopold, Kevin Shannon. (2009) Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature 461:7262, 411-414
CrossRef13
David Viskochil. 2009. Neurofibromatosis Type I (NF1). .
CrossRef14
J. Koenigsmann, C. Rudolph, S. Sander, O. Kershaw, A. D. Gruber, L. Bullinger, B. Schlegelberger, D. Carstanjen. (2009) Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias. Blood 113:19, 4690-4701
CrossRef15
Kaleb Yohay. (2009) Neurofibromatosis type 1 and associated malignancies. Current Neurology and Neuroscience Reports 9:3, 247-253
CrossRef16
Irene Bottillo, Terje Ahlquist, Helge Brekke, Stine A Danielsen, Eva van den Berg, Fredrik Mertens, Ragnhild A Lothe, Bruno Dallapiccola. (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. The Journal of Pathology 217:5, 693-701
CrossRef17
D. Raepple, F. Lintig, T. Zemojtel, M. Duchniewicz, A. Jung, M. Lübbert, G. R. Boss, J. S. Scheele. (2009) Determination of Ras-GTP and Ras-GDP in patients with acute myelogenous leukemia (AML), myeloproliferative syndrome (MPS), juvenile myelomonocytic leukemia (JMML), acute lymphocytic leukemia (ALL), and malignant lymphoma: assessment of mutational and indirect activation. Annals of Hematology 88:4, 319-324
CrossRef18
Rebecca J. Chan, Todd Cooper, Christian P. Kratz, Brian Weiss, Mignon L. Loh. (2009) Juvenile myelomonocytic leukemia: A report from the 2nd International JMML Symposium. Leukemia Research 33:3, 355-362
CrossRef19
Yoshihiro Onoe, Shuji Koike, Takashi Nasu, Daisuke Noda, Akihiro Ishida, Kenichi Ishii, Masaru Aoyagi. (2009) A Case of Leiomyosarcoma of the Nasal Cavity with Neurofibromatosis Type 1. Practica Oto-Rhino-Laryngologica 102:11, 931-937
CrossRef20
Jasmine C. Wong, Michelle M. Le Beau, Kevin Shannon. (2008) Tumor suppressor gene inactivation in myeloid malignancies. Best Practice & Research Clinical Haematology 21:4, 601-614
CrossRef21
Roger McLendon, Allan Friedman, Darrell Bigner, Erwin G. Van Meir, Daniel J. Brat, Gena M. Mastrogianakis, Jeffrey J. Olson, Tom Mikkelsen, Norman Lehman, Ken Aldape, W. K. Alfred Yung, Oliver Bogler, Scott VandenBerg, Mitchel Berger, Michael Prados, Donna Muzny, Margaret Morgan, Steve Scherer, Aniko Sabo, Lynn Nazareth, Lora Lewis, Otis Hall, Yiming Zhu, Yanru Ren, Omar Alvi, Jiqiang Yao, Alicia Hawes, Shalini Jhangiani, Gerald Fowler, Anthony San Lucas, Christie Kovar, Andrew Cree, Huyen Dinh, Jireh Santibanez, Vandita Joshi, Manuel L. Gonzalez-Garay, Christopher A. Miller, Aleksandar Milosavljevic, Larry Donehower, David A. Wheeler, Richard A. Gibbs, Kristian Cibulskis, Carrie Sougnez, Tim Fennell, Scott Mahan, Jane Wilkinson, Liuda Ziaugra, Robert Onofrio, Toby Bloom, Rob Nicol, Kristin Ardlie, Jennifer Baldwin, Stacey Gabriel, Eric S. Lander, Li Ding, Robert S. Fulton, Michael D. McLellan, John Wallis, David E. Larson, Xiaoqi Shi, Rachel Abbott, Lucinda Fulton, Ken Chen, Daniel C. Koboldt, Michael C. Wendl, Rick Meyer, Yuzhu Tang, Ling Lin, John R. Osborne, Brian H. Dunford-Shore, Tracie L. Miner, Kim Delehaunty, Chris Markovic, Gary Swift, William Courtney, Craig Pohl, Scott Abbott, Amy Hawkins, Shin Leong, Carrie Haipek, Heather Schmidt, Maddy Wiechert, Tammi Vickery, Sacha Scott, David J. Dooling, Asif Chinwalla, George M. Weinstock, Elaine R. Mardis, Richard K. Wilson, Gad Getz, Wendy Winckler, Roel G. W. Verhaak, Michael S. Lawrence, Michael O’Kelly, Jim Robinson, Gabriele Alexe, Rameen Beroukhim, Scott Carter, Derek Chiang, Josh Gould, Supriya Gupta, Josh Korn, Craig Mermel, Jill Mesirov, Stefano Monti, Huy Nguyen, Melissa Parkin, Michael Reich, Nicolas Stransky, Barbara A. Weir, Levi Garraway, Todd Golub, Matthew Meyerson, Lynda Chin, Alexei Protopopov, Jianhua Zhang, Ilana Perna, Sandy Aronson, Narayan Sathiamoorthy, Georgia Ren, Jun Yao, W. Ruprecht Wiedemeyer, Hyunsoo Kim, Sek Won Kong, Yonghong Xiao, Isaac S. Kohane, Jon Seidman, Peter J. Park, Raju Kucherlapati, Peter W. Laird, Leslie Cope, James G. Herman, Daniel J. Weisenberger, Fei Pan, David Van Den Berg, Leander Van Neste, Joo Mi Yi, Kornel E. Schuebel, Stephen B. Baylin, Devin M. Absher, Jun Z. Li, Audrey Southwick, Shannon Brady, Amita Aggarwal, Tisha Chung, Gavin Sherlock, James D. Brooks, Richard M. Myers, Paul T. Spellman, Elizabeth Purdom, Lakshmi R. Jakkula, Anna V. Lapuk, Henry Marr, Shannon Dorton, Yoon Gi Choi, Ju Han, Amrita Ray, Victoria Wang, Steffen Durinck, Mark Robinson, Nicholas J. Wang, Karen Vranizan, Vivian Peng, Eric Van Name, Gerald V. Fontenay, John Ngai, John G. Conboy, Bahram Parvin, Heidi S. Feiler, Terence P. Speed, Joe W. Gray, Cameron Brennan, Nicholas D. Socci, Adam Olshen, Barry S. Taylor, Alex Lash, Nikolaus Schultz, Boris Reva, Yevgeniy Antipin, Alexey Stukalov, Benjamin Gross, Ethan Cerami, Wei Qing Wang, Li-Xuan Qin, Venkatraman E. Seshan, Liliana Villafania, Magali Cavatore, Laetitia Borsu, Agnes Viale, William Gerald, Chris Sander, Marc Ladanyi, Charles M. Perou, D. Neil Hayes, Michael D. Topal, Katherine A. Hoadley, Yuan Qi, Sai Balu, Yan Shi, Junyuan Wu, Robert Penny, Michael Bittner, Troy Shelton, Elizabeth Lenkiewicz, Scott Morris, Debbie Beasley, Sheri Sanders, Ari Kahn, Robert Sfeir, Jessica Chen, David Nassau, Larry Feng, Erin Hickey, Jinghui Zhang, John N. Weinstein, Anna Barker, Daniela S. Gerhard, Joseph Vockley, Carolyn Compton, Jim Vaught, Peter Fielding, Martin L. Ferguson, Carl Schaefer, Subhashree Madhavan, Kenneth H. Buetow, Francis Collins, Peter Good, Mark Guyer, Brad Ozenberger, Jane Peterson, Elizabeth Thomson. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:7216, 1061-1068
CrossRef22
Dong Pang, Robert D. Alston, Tim O.B. Eden, Jillian M. Birch. (2008) Cancer risks among relatives of children with Hodgkin and non‐Hodgkin lymphoma. International Journal of Cancer 123:6, 1407-1410
CrossRef23
P D Emanuel. (2008) Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22:7, 1335-1342
CrossRef24
Kenichi Koike, Kazuyuki Matsuda. (2008) Recent advances in the pathogenesis and management of juvenile myelomonocytic leukaemia. British Journal of Haematology 141:5, 567-575
CrossRef25
B. V. Balgobind, P. Van Vlierberghe, A. M. W. van den Ouweland, H. B. Beverloo, J. N. R. Terlouw-Kromosoeto, E. R. van Wering, D. Reinhardt, M. Horstmann, G. J. L. Kaspers, R. Pieters, C. M. Zwaan, M. M. Van den Heuvel-Eibrink, J. P. P. Meijerink. (2008) Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 111:8, 4322-4328
CrossRef26
Anja Brinckmann, Claudia Mischung, Ingelore Bässmann, Jirko Kühnisch, Markus Schuelke, Sigrid Tinschert, Peter Nürnberg. (2007) Detection of novelNF1 mutations and rapid mutation prescreening with Pyrosequencing. ELECTROPHORESIS 28:23, 4295-4301
CrossRef27
R A Van Etten. (2007) Aberrant cytokine signaling in leukemia. Oncogene 26:47, 6738-6749
CrossRef28
C Flotho, D Steinemann, C G Mullighan, G Neale, K Mayer, C P Kratz, B Schlegelberger, J R Downing, C M Niemeyer. (2007) Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11. Oncogene 26:39, 5816-5821
CrossRef29
Andrea I. McClatchey. (2007) Neurofibromatosis. Annual Review of Pathology: Mechanisms of Disease 2:1, 191-216
CrossRef30
C R Hake, T A Graubert, T S Fenske. (2007) Does autologous transplantation directly increase the risk of secondary leukemia in lymphoma patients?. Bone Marrow Transplantation 39:2, 59-70
CrossRef31
Eric Knoche, Howard L McLeod, Timothy A Graubert. (2006) Pharmacogenetics of alkylator-associated acute myeloid leukemia. Pharmacogenomics 7:5, 719-729
CrossRef32
Jennifer O. Lauchle, Benjamin S. Braun, Mignon L. Loh, Kevin Shannon. (2006) Inherited predispositions and hyperactive Ras in myeloid leukemogenesis. Pediatric Blood & Cancer 46:5, 579-585
CrossRef33
K Matsuda, S Matsuzaki, J Miki, E Hidaka, R Yanagisawa, Y Nakazawa, K Sakashita, T Kamijo, K Asami, K Sano, K Koike. (2006) Chromosomal change during 6-mercaptopurine (6-MP) therapy in juvenile myelomonocytic leukemia: the growth of a 6-MP-refractory clone that already exists at onset. Leukemia 20:3, 485-490
CrossRef34
Suzanne Schubbert, Martin Zenker, Sara L Rowe, Silke Böll, Cornelia Klein, Gideon Bollag, Ineke van der Burgt, Luciana Musante, Vera Kalscheuer, Lars-Erik Wehner, Hoa Nguyen, Brian West, Kam Y J Zhang, Erik Sistermans, Anita Rauch, Charlotte M Niemeyer, Kevin Shannon, Christian P Kratz. (2006) Germline KRAS mutations cause Noonan syndrome. Nature Genetics 38:3, 331-336
CrossRef35
Seon-Yong Jeong, Sang-Jin Park, Hyon J. Kim. (2006) The Spectrum of NF1 Mutations in Korean Patients with Neurofibromatosis Type 1. Journal of Korean Medical Science 21:1, 107
CrossRef36
Oren N. Gottfried, David H. Viskochil, Daniel W. Fults, William T. Couldwell. (2006) Molecular, Genetic, and Cellular Pathogenesis of Neurofibromas and Surgical Implications. Neurosurgery 58:1, 1-16
CrossRef37
David Viskochil. 2005. Neurofibromatosis Type 1. .
CrossRef38
Ghulam J. Mufti. (2004) Pathobiology, classification, and diagnosis of myelodysplastic syndrome. Best Practice & Research Clinical Haematology 17:4, 543-557
CrossRef39
M Tadin-Strapps, D Warburton, JC Salas-Alanis, LD Lopez-Cepeda, AM Christiano. (2004) Fishing for new genes in skin biology: impact of cytogenetics on gene discovery. Clinical Genetics 66:2, 94-106
CrossRef40
Kelly Hiatt, David A. Ingram, Hannah Huddleston, Dan F. Spandau, Reuben Kapur, D. Wade Clapp. (2004) Loss of the Nf1 Tumor Suppressor Gene Decreases Fas Antigen Expression in Myeloid Cells. The American Journal of Pathology 164:4, 1471-1479
CrossRef41
Yu-Hsiang Chang, Shiann-Tarng Jou, Dong-Tsamn Lin, Meng-Yao Lu, Kai-Hsin Lin. (2004) Differentiating Juvenile Myelomonocytic Leukemia From Chronic Myeloid Leukemia in Childhood. Journal of Pediatric Hematology/Oncology 26:4, 236-242
CrossRef42
Meena Upadhyaya, Song Han, Claudia Consoli, Elisa Majounie, Martin Horan, Nick S. Thomas, Christopher Potts, Sian Griffiths, Martino Ruggieri, Andreas von Deimling, David N. Cooper. (2004) Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 ( NF1 ) gene in neurofibromatosis patients with benign and malignant tumors. Human Mutation 23:2, 134-146
CrossRef43
Marco Tartaglia, Charlotte M. Niemeyer, Kevin M. Shannon, Mignon L. Loh. (2004) SHP-2 and myeloid malignancies. Current Opinion in Hematology 11:1, 44-50
CrossRef44
Charlotte Marie Niemeyer, Christian Kratz. (2003) Juvenile myelomonocytic leukemia. Current Oncology Reports 5:6, 510-515
CrossRef45
Charlotte Marie Niemeyer, Christian Kratz. (2003) Juvenile myelomonocytic leukemia. Current Treatment Options in Oncology 4:3, 203-210
CrossRef46
Christian P. Kratz, Letizia Antonietti, Kevin M. Shannon, Mukund G. Dole, Sarah E. Friebert. (2003) Acute Myeloid Leukemia Associated With t(8;21) or Trisomy 8 in Children With Neurofibromatosis, Type 1. Journal of Pediatric Hematology/Oncology 25:4, 343
CrossRef47
Biplab Dasgupta, David H Gutmann. (2003) Neurofibromatosis 1: closing the GAP between mice and men. Current Opinion in Genetics & Development 13:1, 20-27
CrossRef48
David P Steensma, Ayalew Tefferi. (2003) The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leukemia Research 27:2, 95-120
CrossRef49
Elaine W. Leung, Wilma Vanek, Mohamed Abdelhaleem, Melvin H. Freedman, Yigal Dror. (2003) The Evolution of Juvenile Myelomonocytic Leukemia in a Female Patient with Paternally Inherited Neurofibromatosis Type 1. Journal of Pediatric Hematology/Oncology 25:2, 145-147
CrossRef50
Di Lu, Randa Nounou, Miloslav Beran, Elihu Estey, Taghi Manshouri, Hagop Kantarjian, Michael J. Keating, Maher Albitar. (2003) The prognostic significance of bone marrow levels of neurofibromatosis-1 protein and ras oncogene mutations in patients with acute myeloid leukemia and myelodysplastic syndrome. Cancer 97:2, 441-449
CrossRef51
James R Downing, Kevin M Shannon. (2002) Acute leukemia: A pediatric perspective. Cancer Cell 2:6, 437-445
CrossRef52
Kenneth D. McMilin. (2002) Allogeneic hematopoietic stem cell transplantation and the risk for transmission of heritable malignancy. Transfusion 42:4, 495-504
CrossRef53
Petra Braam, Cornelus J. G. Sanders, Marijke R. Canninga-van Dijk. (2002) Neurofibromatosis type 1 and mycosis fungoides. International Journal of Dermatology 41:4, 236-238
CrossRef54
Hisamaru Hirai. (2002) Molecular pathogenesis of MDS. International Journal of Hematology 76:S2, 213-221
CrossRef55
Shane Donovan, Kevin M. Shannon, Gideon Bollag. (2002) GTPase activating proteins: critical regulators of intracellular signaling. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1602:1, 23-45
CrossRef56
Christian P Kratz, Brooke M Emerling, Shane Donovan, Marion Laig-Webster, Brigit R Taylor, Patricia Thompson, Sanford Jensen, Anuradha Banerjee, Jeannette Bonifas, Wojciech Makalowski, Eric D Green, Michelle M Le Beau, Kevin M Shannon. (2001) Candidate Gene Isolation and Comparative Analysis of a Commonly Deleted Segment of 7q22 Implicated in Myeloid Malignancies. Genomics 77:3, 171-180
CrossRef57
Georgina W. Hall. (2001) Childhood myeloid leukaemias. Best Practice & Research Clinical Haematology 14:3, 573-591
CrossRef58
Youyan Zhang, Brigit R. Taylor, Kevin Shannon, D. Wade Clapp. (2001) Quantitative effects of Nf1 inactivation on in vivo hematopoiesis. Journal of Clinical Investigation 108:5, 709-715
CrossRef59
Kevin M Shannon, Michelle M Le Beau, David A Largaespada, Nigel Killeen. (2001) Modeling myeloid leukemia tumor suppressor gene inactivation in the mouse. Seminars in Cancer Biology 11:3, 191-200
CrossRef60
Pierre Fenaux. (2001) Chromosome and Molecular Abnormalities in Myelodysplastic Syndromes. International Journal of Hematology 73:4, 429-437
CrossRef61
Nevada Reed, David H. Gutmann. (2001) Tumorigenesis in neurofibromatosis: new insights and potential therapies. Trends in Molecular Medicine 7:4, 157-162
CrossRef62
Peter B. Langmuir, Richard Aplenc, Beverly J. Lange. (2001) Acute myeloid leukaemia in children. Best Practice & Research Clinical Haematology 14:1, 77-93
CrossRef63
Andrea I. McClatchey, Karen Cichowski. (2001) Mouse models of neurofibromatosis. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1471:2, M73-M80
CrossRef64
Giuseppe Leone, Maria Teresa Voso, Simona Sica, Roberta Morosetti, Livio Pagano. (2001) Therapy Related Leukemias: Susceptibility, Prevention and Treatment. Leukemia & Lymphoma 41:3-4, 255-276
CrossRef65
Maha M. Lakkis, Gihan I. Tennekoon. (2000) Neurofibromatosis type 1 I. General overview. Journal of Neuroscience Research 62:6, 755-763
CrossRef66
Olubunmi Afonja, John E. Smith Jr., Debbie M. Cheng, Alec S. Goldenberg, Edward Amorosi, Takashi Shimamoto, Shuji Nakamura, Kazuma Ohyashiki, Junko Ohyashiki, Keisuke Toyama, Kenichi Takeshita. (2000) MEIS1 and HOXA7 genes in human acute myeloid leukemia. Leukemia Research 24:10, 849-855
CrossRef67
Sonja A. Rasmussen, Jennifer Overman, Susanne A.M. Thomson, Steven D. Colman, Corinne R. Abernathy, Rachael E. Trimpert, Rebecca Moose, Gurinder Virdi, Kyle Roux, Mislen Bauer, Amyn M. Rojiani, Bernard L. Maria, David Muir, Margaret R. Wallace. (2000) Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1. Genes, Chromosomes and Cancer 28:4, 425-431
CrossRef68
D. H. Gutmann, J. Donahoe, T. Brown, C. D. James, A. Perry. (2000) Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathology and Applied Neurobiology 26:4, 361-367
CrossRef69
Ludwine M. Messiaen, Tom Callens, Geert Mortier, Diane Beysen, Ina Vandenbroucke, Nadine Van Roy, Frank Speleman, Anne De Paepe. (2000) Exhaustive mutation analysis of theNF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Human Mutation 15:6, 541-555
CrossRef70
Margaret R. Wallace, Sonja A. Rasmussen, Ingrid T. Lim, Brian A. Gray, Roberto T. Zori, David Muir. (2000) Culture of cytogenetically abnormal Schwann cells from benign and malignant NF1 tumors. Genes, Chromosomes and Cancer 27:2, 117-123
CrossRef71
Ron A. Birnbaum, Aengus O'Marcaigh, Zabihullah Wardak, You-Yan Zhang, Glenn Dranoff, Tyler Jacks, D.Wade Clapp, Kevin M. Shannon. (2000) Nf1 and Gmcsf Interact in Myeloid Leukemogenesis. Molecular Cell 5:1, 189-195
CrossRef72
Rina Wu, Catalina L
pez-Correa, J. Lynn Rutkowski, Lisa L. Baumbach, Thomas W. Glover, Eric Legius. (1999) Germline mutations in NF1 patients with malignancies. Genes, Chromosomes and Cancer 26:4, 376-380
CrossRef73
Jun Miyauchi, Minoru Asada, Yukiko Tsunematsu, Yasuhiko Kaneko, Seiji Kojima, Shuki Mizutani. (1999) Abnormalities of the p53 gene in juvenile myelomonocytic leukaemia. British Journal of Haematology 106:4, 980-986
CrossRef74
Carol L. Clericuzio. (1999) Recognition and management of childhood cancer syndromes: A systems approach. American Journal of Medical Genetics 89:2, 81-90
CrossRef75
Peter D. Emanuel. (1999) Myelodysplasia and myeloproliferative disorders in childhood: an update. British Journal of Haematology 105:4, 852-863
CrossRef76
Brian Weiss, Gideon Bollag, Kevin Shannon. (1999) Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. American Journal of Medical Genetics 89:1, 14-22
CrossRef77
P S Karnes. (1998) Neurofibromatosis: a common neurocutaneous disorder.. Mayo Clinic Proceedings 73:11, 1071-1076
CrossRef78
A. Mijović, G.J. Mufti. (1998) The myelodysplastic syndromes: towards a functional classification. Blood Reviews 12:2, 73-83
CrossRef79
Cristina Mecucci. (1998) Molecular features of primary MDS with cytogenetic changes. Leukemia Research 22:4, 293-302
CrossRef80
Byrne, Marshall. (1998) THE MOLECULAR PATHOPHYSIOLOGY OF MYELOID LEUKAEMIAS: Ras REVISITED. British Journal of Haematology 100:2, 256-264
CrossRef81
Aengus S. OʼMarcaigh, Kevin M. Shannon. (1997) Role of the NF1 Gene in Leukemogenesis and Myeloid Growth Control. Journal of Pediatric Hematology/Oncology 19:6, 551-554
CrossRef
