A new genetic lesion in B‐CLL: a <i>NOTCH1</i> PEST domain mutation

Ianni, Mauro Di; Baldoni, Stefano; Rosati, Emanuela; Ciurnelli, Raffaella; Cavalli, Laura; Martelli, Massimo F.; Marconi, Pierfrancesco; Screpanti, Isabella; Falzetti, Franca

doi:10.1111/j.1365-2141.2009.07816.x

Cited by 97 publications

(83 citation statements)

References 10 publications

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“…This latter type of mutations are found in CLL, especially as a frameshift mutation affecting the codon for amino-acid P2515. 4,7,61 Comparable NOTCH1 mutations are also found in B-cell lymphomas 62 and both activation and inactivation of the pathway have been identified in hematopoietic and non-hematopoietic diseases. 63 As with T-cell acute lymphoblastic leukemia, mutations inactivating the FBXW7 gene, which codes normal feedback control of Notch signaling (which also control CMYC stability 64 ), are also observed in CLL.…”

Section: Other Novel Mutations In Lymphomasmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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Section: Other Novel Mutations In Lymphomasmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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“…7,8 By this approach, NOTCH1 mutations occurred in only 2 of 63 (3.2%) cMBL, with a prevalence that was significantly lower than that observed in a large CLL dataset (70 of 603, 11.6%) (P=0.050). In both cases, mutations were represented by a two bp frameshift deletion (c.7544_7545delCT) that represents the most recurrent (~80%) type of NOTCH1 mutation detectable in CLL (Figure 1).…”

Section: Analysis Of Notch1 Mutations In Monoclonal B-cell Lymphocytosismentioning

confidence: 99%

“…[4][5][6] Recently, two independent investigations of the CLL coding genome have revealed that activating mutations of the NOTCH1 proto-oncogene occur in approximately 10% CLL at diagnosis and their frequency increases in advanced disease phases, exemplified by the case of Richter syndrome. 7,8 Initial evidence suggests that NOTCH1 alterations might predict an unfavorable clinical outcome in CLL. The prevalence of NOTCH1 mutations in MBL is currently unknown.…”

Section: Analysis Of Notch1 Mutations In Monoclonal B-cell Lymphocytosismentioning

confidence: 99%

“…The prevalence of NOTCH1 mutations in MBL is currently unknown. [7][8][9][10][11] Here we investigated the occurrence of NOTCH1 mutations in 63 consecutive cMBL presenting at our clinic for the initial evaluation of an asymptomatic lymphocytosis. The cMBL cohort was provided with prospectively collected peripheral blood mononuclear cell samples drawn at presentation, and with a prospectively maintained clinical database.…”

Section: Analysis Of Notch1 Mutations In Monoclonal B-cell Lymphocytosismentioning

confidence: 99%

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Analysis of NOTCH1 mutations in monoclonal B-cell lymphocytosis

Rasi¹,

Monti²,

Spina³

et al. 2011

Haematologica

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“…Dans les LAL-T, les mutations de NOTCH1 peuvent soit faciliter la dissociation de la partie intracellulaire ICN de NOTCH1, soit entraî-ner la perte du domaine PEST de déstabi-lisation de ICN. Ce sont des mutations de ce dernier type qui sont présentes dans les LLC, principalement une mutation « saut de phase » touchant le codon correspondant à l'acide aminé P2515 [9][10][11]. Des mutations de NOTCH1 sont également trouvées dans les lymphomes.…”

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