GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Society of Hematology  (3)
  • Zenker, Martin  (3)
  • 1
    Online Resource
    Online Resource
    BRAF Mutations in Juvenile Myelomonocytic Leukemia.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 4602-4602
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 4602-4602
    Abstract: Approximately 75% of patients with juvenile myelomonocytic leukemia (JMML) harbour mutations in PTPN11, NF1 and RAS genes. The remaining cases presumably carry somatic mutations in other genes in the RAS pathway. BRAF plays a central role in this pathway between RAS and downstream molecules including MEK and ERK. BRAF mutations frequently occur in cancer. Recently, BRAF mutations were found in leukemia. Besides that, germline BRAF mutations cause cardio-facio-cutaneous syndrome, which shares many features with Noonan syndrome (NS). NS predisposes to a myeloproliferative disease resembling JMML. In 65 JMML patients screening for V600E mutations in exon 15 of the BRAF gene was performed from mononuclear cells. In a subset of patients, without RAS or PTPN11 mutations, and no clinical signs of NF1, the entire coding sequence of BRAF was analyzed. Sequence analysis was performed by direct, bidirectional sequencing of purified polymerase chain reaction products. In none of the 65 cases a V600E mutation of the BRAF gene was found. In a subset of patients in which the entire coding sequence of BRAF was analyzed, no mutations were identified either. Mutant proteins of the RAS-RAF-MEK-ERK pathway play an important role in the pathogenesis of JMML, resulting in GM-CSF hypersensitivity. In about 75% of the JMML cases these mutations affect RAS, NF1 or PTPN11 genes. The hypothesis for this study was that BRAF might play an important role in JMML as it is an important downstream effector of RAS. Our data show that apparently BRAF mutations do not play a role in JMML. Therefore, additional analysis of genes of the RAS pathway will be necessary to identify genetic aberrations in cases without known mutations.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.4602.4602
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Novel Germ Line Mutations in the KRAS2 Gene Cause Noonan Syndrome and Deregulate Hematopoietic Cell Growth.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1602-1602
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1602-1602
    Abstract: RAS genes encode 21-kDa signal switch molecules that regulate cell fates by cycling between inactive GDP-bound (Ras-GDP) and active GTP-bound (Ras-GTP) conformations. Cancer-associated somatic mutations lead to substitutions at codons G12, G13, or Q61 that impair the intrinsic Ras GTPase and confer resistance to GTPase-activating proteins (GAPs). Noonan syndrome (NS) is an autosomal dominant developmental disorder characterized by short stature, facial dysmorphism, and variable congenital cardiac defects. Infants with NS are predisposed to hematologic disorders including juvenile myelomonocytic leukemia (JMML). In ~50% of patients, NS is caused by mutations in the PTPN11 gene. PTPN11 encodes SHP-2, a non receptor protein-tyrosine phosphatase (PTPase) that relays signals from growth factor receptors to Ras and other signaling molecules. Interestingly, somatic PTPN11 mutations that cause aberrant PTPase activity are found in ~35% of JMML bone marrows from patients without NS and occur at lower frequency in other hematologic malignancies (Tartaglia and Niemeyer et alia, Nat Genet34, 148, 2003; Loh et alia, Blood103, 2325, 2004). We identified a patient with NS and JMML who did not have a PTPN11 mutation. Instead, molecular analysis revealed a novel de novo germ line mutation in KRAS2, c.173C & gt;T, which introduces a T58I substitution within the K-Ras protein. We then screened DNA samples from 124 NS patients that did not show PTPN11 mutations for alterations in HRAS, NRAS, and KRAS2. These studies uncovered a second novel de novo KRAS2 mutation (c.40G & gt;A) in 3 unrelated cases, which predicts a V14I substitution in the phosphate-binding loop of the protein. We expressed the mutant K-Ras T58I and V14I proteins in COS-7 cells and measured Ras-GTP levels and the activation of Ras effectors. Whereas K-Ras V14I-accumulated in the GTP-bound conformation in both basal and starved conditions and was associated with hyper-phosphorylation of MEK, the T58I mutant protein did not dramatically alter Ras-GTP levels in this system. By contrast, expressing T58I and V14I K-Ras in primary murine hematopoietic cells induced a hypersensitive pattern of granuocyte-macrophage colony forming unit (CFU-GM) growth in response to granulocyte-macrophage colony stimulating factor (GM-CSF), which was more pronounced for the T58I mutant protein. T58I-expressing cells also exhibited enhanced erythroid progenitor colony growth. These studies establish germ line KRAS2 mutations as a cause of NS. While the more severe effects of T58I K-Ras on hematopoietic growth are consistent with the occurrence of JMML in the proband, the stronger biochemical phenotype of V14I K-Ras in COS-7 cells suggests that cell context strongly modulates the activation state of these mutant proteins. Ongoing in vitro experiments in which we are measuring the intrinsic rates of GTP hydrolysis of recombinant T58I and V14I K-Ras and comparing their sensitivities to GAPs will further elucidate the functional consequences of these novel disease-associated mutations.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1602.1602
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Inherited Disorders of the Ras-MAPK Pathway
    American Society of Hematology ; 2018
    In:  Blood Vol. 132, No. Supplement 1 ( 2018-11-29), p. SCI-41-SCI-41
    Details
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. SCI-41-SCI-41
    Abstract: RASopathies are a group of rare congenital diseases in which dysregulated signaling through the RAS-MAPK signaling cases is the critical pathogenetic mechanism. This definition excludes postnatally acquired conditions (e.g. RAS-MAPK driven neoplasms) and PIK3-AKT pathway related disorders as well as conditions with only ancillary RAS pathway involvement (e.g. KAT6B-, RAP1A/B-related disorders). The definition, however, includes the following categories: (1) Noonan syndrome and related disorders, specifically Noonan syndrome (NS), NS with multiple lentigines, NS-like disorder with loose anagen hair, CBL syndrome, cardiofaciocutaneous syndrome, and Costello syndrome); (2) Neurofibromatosis type 1 and the related disorders Neurofibromatosis-Noonan syndrome and Legius syndrome; (3) Mosaic RASopathies including a rapidly growing group of mainly (neuro)cutaneous disorders with "oncogenic" mutations in a somatic mosaic state; (4) RAS-MAPK pathway dysregulation without a NS-like phenotype including non-syndromic intellectual disability due to SYNGAP1mutations and capillary malformation-arteriovenous malformation/Parkes-Weber syndrome; (5) RAS-MAPK pathway defects without overactivation such as metachondromatosis. Germline mutations leading to Ras-MAPK dysregulation typically lead to a characteristic pattern of craniofacial anomalies, heart defects, shorts stature, and variable neurodevelopmental deficits as seen in NS and other RASopathies of category 1. Confirmed genes leading to RASopathies from this category include BRAF,CBL, HRAS, KRAS, MAP2K1, MAP2K1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1, LZTR1, and PPP1CB. Newer genes include SOS2, MRAS, RRAS, and RASA2. For some individual RASopathy disease entities, specific genotype associations exist, for others, this correlation is not tight. The cancer risk in many patients with RASopathies is only moderately increased, however, for a subgroup of patients the cancer risk is very high. These include patients with Costello syndrome (HRAS) who develop rhabdomyosarcoma, neuroblastoma and bladder cancer, patients with NF1 who develop juvenile myelomonocytic leukemia (JMML), neurofibroma/-fibrosarcoma, and brain tumors, and patients and with CBL syndrome who develop JMML. New clinical studies explore the use of RAS-MAPK Pathway inhibitors in this unique population. Various animal and in vitro models have been described, which (partially) recapitulate the human RASopathy phenotype and phenotypic rescue by manipulating RAS-MAPK signal flow has been demonstrated. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2018-99-109379
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...