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

Giudice, Ilaria Del; Rossi, Davide; Chiaretti, Sabina; Marinelli, M; Tavolaro, Simona; Gabrielli, Sara; Laurenti, Luca; Marasca, Roberto; Rasi, Silvia; Fangazio, Marco; Guarini, Anna; Gaïdano, Gianluca; Foà, Robin

doi:10.3324/haematol.2011.060129

Cited by 173 publications

(166 citation statements)

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“…15 In this issue of Haematologica, Del Giudice and colleagues document a high frequency of NOTCH1 mutations in CLL cases harboring trisomy 12 as the sole cytogenetic abnormality (30%). 7 Importantly, this study also reveals a significant shortening of survival in the NOTCH1 mutation positive patients, refining the intermediate prognosis of CLL cases with trisomy 12. Moreover, this study highlights that the presence of NOTCH1 mutations in +12 CLL cases is associated with a peculiar gene-expression profile characterized by an overrepresentation of cell cycle related genes that are located on chromosome 12.…”

Section: 2mentioning

confidence: 89%

“…The observation of a high expression of IgM in the group harboring NOTCH1 mutations also suggests that those alterations occur preferentially in cells highly responsive to external stimuli and sustaining NOTCH1 signaling. 7 It remains to be determined whether NOTCH1 mutations represent a primary event occurring in the first stage of transformation or a secondary event driving disease progression. Using deep sequencing of paired samples at diagnosis and RS, it was confirmed that, in some cases, NOTCH1 mutations can be detected in subclones.…”

Section: 2mentioning

confidence: 99%

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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: 89%

Section: 2mentioning

confidence: 99%

Activation of the NOTCH1 pathway in chronic lymphocytic leukemia

Gianfelici¹

2012

Haematologica

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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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“…In CLL, besides TP53 and ATM mutations, which are both known to confer poor prognosis, recent high-throughput NGS studies have revealed recurrent mutations within NOTCH1, SF3B1, and BIRC3 for example, that were reported to be associated with poor clinical outcome with higher frequencies in relapsing/treatment-refractory CLL and in Richter's syndrome. 48,[69][70][71][72][73][74][75][76][77][78][79] More recent studies have also identified additional gene mutations that may confer a worse outcome in CLL, e.g. NKFBIE, EGR2, and RPS15, although they have been studied less.…”

Section: Genes With Prognostic Potentialmentioning

confidence: 99%