Loss of <scp>CBL</scp> E3‐ligase activity in B‐lineage childhood acute lymphoblastic leukaemia

Martinelli, Simone; Checquolo, Saula; Consoli, Federica; Stellacci, Emilia; Rossi, Cesare; Silvano, Marianna; Franciosa, Giulia; Flex, Elisabetta; Cossu, Carla; Luca, Alessandro De; Foà, Robin; Cazzaniga, Giovanni; Biondi, Andrea; Screpanti, Isabella; Tartaglia, Marco

doi:10.1111/j.1365-2141.2012.09245.x

Cited by 7 publications

(10 citation statements)

References 9 publications

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“…Screening of CBL in an unselected cohort of ALL patients identified somatic mutations in 1–2% of cases (48, 49). Mutations have also been reported in T ALL and infant ALL and are often associated with acquired uniparental disomy at the CBL gene locus, resulting in a homozygous mutant state (49–51). Functional analyses have shown mutations to be associated with stabilization of RTK receptors in an active state, constitutive activation of the Ras pathway, and cellular sensitivity to MEK inhibitor (MEKi) treatment.…”

Section: Mechanisms Of Ras Pathway Activation In Allmentioning

confidence: 99%

Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting

2014

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Deregulation of the Ras/Raf/MEK/extracellular signal-regulated kinase pathway is a common event in childhood acute lymphoblastic leukemia and is caused by point mutation, gene deletion, and chromosomal translocation of a vast array of gene types, highlighting its importance in leukemia biology. Pathway activation can be therapeutically exploited and may guide new therapies needed for relapsed acute lymphoblastic leukemia and other high risk subgroups.

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Section: Mechanisms Of Ras Pathway Activation In Allmentioning

confidence: 99%

Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting

2014

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“…Of these 15 genes, eleven have been found to be involved in NS or NS-like conditions, where mutations in PTPN11 are the cause of ~50 % of the cases. The other genes are SOS1 [ 3 , 4 ] , CBL [ 5 – 7 ] , BRAF [ 8 ] , RAF1 [ 9 , 10 ] , SHOC2 [ 11 ] , MAP2K1 [ 12 ] , RIT1 [ 13 ] , NRAS [ 14 ], KRAS [ 15 , 16 ] and RRAS [ 17 ] .…”

Section: Introductionmentioning

confidence: 99%

Mutation in NRAS in familial Noonan syndrome – case report and review of the literature

et al. 2015

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BackgroundNoonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway.Case presentationHere, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient’s father, who also showed signs of NS.ConclusionsWe describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50 % of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

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“…Collected data indicate that disease‐associated mutations are predominantly splice site or missense changes affecting exons 8 and 9, which encode the RING finger domain and/or the adjacent linker helix region (LHR) connecting this domain to the N ‐terminal tyrosine kinase binding (TKB) domain. In line with studies focused on cancer‐associated CBL mutations [Sargin et al., ; Sanada et al., ; Martinelli et al., ], functional characterization of a panel of RASopathy‐causing mutants documented that lesions act in a dominant‐negative manner, affecting CBL‐mediated receptor ubiquitination, and upregulate signal flow through RAS [Martinelli et al., ; Niemeyer et al., ; Brand et al., ].…”

Section: Introductionmentioning

confidence: 79%

“…Twenty‐four hours post‐transfection, cells were serum‐starved (16 hr) and then stimulated with EGF (Life Technologies) (100 ng/ml, 30 min). ERK and AKT phosphorylation assays were performed in cells transiently expressing the p.Tyr235*, p.Arg420Gln, and wild‐type CBL proteins, as previously described [Martinelli et al., , ]. Protein phosphorylation status (pERK1/2 #9106 and pAKT #9271S; Cell Signaling, Danvers, MA) was evaluated basally or after EGF stimulation.…”

Section: Methodsmentioning

confidence: 99%

Molecular Diversity and Associated Phenotypic Spectrum of GermlineCBLMutations

et al. 2015

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Noonan syndrome (NS) is a relatively common developmental disorder with a pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as a tumor suppressor in myeloid malignancies, as a disease gene underlying a condition clinically related to NS. Here, we further explored the spectrum of germline CBL mutations and their associated phenotype. CBL mutation scanning performed on 349 affected subjects with features overlapping NS and no mutation in NS genes allowed the identification of five different variants with pathological significance. Among them, two splice-site changes, one in-frame deletion, and one missense mutation affected the RING domain and/or the adjacent linker region, overlapping cancer-associated defects. A novel nonsense mutation generating a v-Cbl-like protein able to enhance signal flow through RAS was also identified. Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism. Finally, we excluded a major contribution of two additional members of the CBL family, CBLB and CBLC, to NS and related disorders.

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Loss of CBL E3‐ligase activity in B‐lineage childhood acute lymphoblastic leukaemia

Cited by 7 publications

References 9 publications

Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting

Ras/Raf/MEK/ERK Pathway Activation in Childhood Acute Lymphoblastic Leukemia and Its Therapeutic Targeting

Mutation in NRAS in familial Noonan syndrome – case report and review of the literature

Molecular Diversity and Associated Phenotypic Spectrum of GermlineCBLMutations

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