<i>NOTCH1</i> PEST domain mutation is an adverse prognostic factor in B‐CLL

Sportoletti, Paolo; Baldoni, Stefano; Cavalli, Laura; Papa, Beatrice Del; Bonifacio, Elisabetta; Ciurnelli, Raffaella; Bell, Alain Sylvin; Tommaso, Ambra Di; Rosati, Emanuela; Crescenzi, Barbara; Mecucci, Cristina; Screpanti, Isabella; Marconi, Pierfrancesco; Martelli, Massimo F.; Ianni, Mauro Di; Falzetti, Franca

doi:10.1111/j.1365-2141.2010.08368.x

Cited by 97 publications

(86 citation statements)

References 9 publications

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“…13 Recently, using next-generation sequencing technologies, different groups discovered that 4% of CLL patients also harbor NOTCH1 mutations ( Table 1), indicating that mutations could be one of the mechanisms explaining NOTCH activation in this disease. [3][4][5]14 Different to T-ALL, the mutations almost exclusively occur in exon 34 and usually generate a premature stop codon resulting in a constitutively active and more stable NOTCH1 protein lacking the Cterminal PEST domain. A recurrent CT deletion (p.P2515fs4) was found in around 80% of NOTCH1 mutation positive CLL cases, and a PCR based strategy has been designed for its rapid detection.…”

Section: 2mentioning

confidence: 99%

Activation of the NOTCH1 pathway in chronic lymphocytic leukemia

Gianfelici¹

2012

Haematologica

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328haematologica | 2012; 97(3) Figure 1. Schematic representation of the NOTCH1 receptor. The extracellular domain of NOTCH1 consists of 36 epidermal growth factor-like repeats (EGFR) followed by 3 cysteine-rich lin12/Notch repeats (LNR) and the heterodimerization domain (HD). Upon transport to the plasmamembrane, NOTCH1 is cleaved in two units, which are kept together by interactions between the HD domains. Upon binding of the ligand, NOTCH1 is further cleaved by the gamma-secretase complex, resulting in release of the intracellular part (ICN1). ICN1 can then move to the nucleus where it functions in a transcriptional complex. ICN1 contains the RAM domain (R), ankyrine repeats, transactivation domain (TAD) and the PEST sequence that tags ICN1 for degradation by FBXW7. S2: proteolitic site for Metalloprotease; S3: gamma-secretase cleavage site.

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Section: 2mentioning

confidence: 99%

Activation of the NOTCH1 pathway in chronic lymphocytic leukemia

Gianfelici¹

2012

Haematologica

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“…5,6 The prevalence of NOTCH1 mutations increases with disease aggressiveness. 5 At diagnosis, NOTCH1 mutations show an adverse impact on outcome, confirmed in at least four series, [4][5][6][7] and act independently of other clinico-biological features, including TP53 disruption. 7 Among CLL cytogenetic subgroups, NOTCH1 mutations are distributed in a mutually exclusive fashion with TP53 disruption and are enriched in CLL carrying +12, where they recur in approximately 25% of patients.…”

Section: Introductionmentioning

confidence: 99%

“…1 The NOTCH1 gene has been shown to have an essential biological role in hematopoiesis. 3 Following the pivotal study that identified NOTCH1 mutations in CLL and provided initial evidence on the unfavorable clinical outcome associated with NOTCH1 alterations, 4 two independent studies of the CLL coding genome have recently identified activating mutations of the NOTCH1 gene in approximately 10% of CLL at diagnosis. 5,6 The prevalence of NOTCH1 mutations increases with disease aggressiveness.…”

Section: Introductionmentioning

confidence: 99%

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL

Giudice¹,

Rossi²,

Chiaretti³

et al. 2011

Haematologica

173

128

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“…In some series, mutations of NOTCH1 and FBXW7 are associated with the presence of trisomy 12 and the nonmutated status of the hypervariable regions of immunoglobulin genes. [65][66][67][68] MYD88 is mutated in CLL, the most frequent mutations being L265P mutation, as in B-cell lymphoma. 69 MYD88 missense mutations are activator type mutations that result in the constitutive activation of the transcription factors STAT3 and NFkB.…”

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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NOTCH1 PEST domain mutation is an adverse prognostic factor in B‐CLL

Abstract: [No abstract available

Cited by 97 publications

References 9 publications

Activation of the NOTCH1 pathway in chronic lymphocytic leukemia

Activation of the NOTCH1 pathway in chronic lymphocytic leukemia

NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL

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

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