A wide role for NOTCH1 signaling in acute leukemia

Chiaramonte, Raffaella; Basile, Andrea; Tassi, Elena; Calzavara, Elisabetta; Cecchinato, Valentina; Rossi, Vincenzo; Biondi, Andrea; Comi, Paola

doi:10.1016/j.canlet.2004.07.022

Cited by 68 publications

(53 citation statements)

References 26 publications

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“…The involvement of Notch pathway in B-cell malignancies is not well understood. In general, BCP-ALLs show lower NOTCH expression than T-ALLs (Chiaramonte et al, 2005), whereas B-cell derived Hodgkin lymphoma cells showed overexpression of both NOTCH and JAG1 (Jundt et al, 2002). Larger studies and further functional analyses are needed to understand the biological role of JAG1 up-regulation in ETV6-related leukemia, and to define whether this aberration is related to the isolated ETV6 deletion, in association with the t(12;21) translocation or with the chromosome 21 aberrations (iAMP21 or trisomy 21).…”

Section: Discussionmentioning

confidence: 94%

Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks

Bungaro

Dell’Orto

Zangrando

et al. 2008

Genes Chromosomes & Cancer

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Pediatric acute lymphoblastic leukemia (ALL) comprises genetically distinct subtypes. However, 25% of cases still lack defined genetic hallmarks. To identify genomic aberrancies in childhood ALL patients nonclassifiable by conventional methods, we performed a single nucleotide polymorphisms (SNP) array-based genomic analysis of leukemic cells from 29 cases. The vast majority of cases analyzed (19/24, 79%) showed genomic abnormalities; at least one of them affected either genes involved in cell cycle regulation or in B-cell development. The most relevant abnormalities were CDKN2A/9p21 deletions (7/24, 29%), ETV6 (TEL)/12p13 deletions (3/24, 12%), and intrachromosomal amplifications of chromosome 21 (iAMP21) (3/24, 12%). To identify variation in expression of genes directly or indirectly affected by recurrent genomic alterations, we integrated genomic and gene expression data generated by microarray analyses of the same samples. SMAD1 emerged as a down-regulated gene in CDKN2A homozygous deleted cases compared with nondeleted. The JAG1 gene, encoding the Jagged 1 ligand of the Notch receptor, was among a list of differentially expressed (up-regulated) genes in ETV6-deleted cases. Our findings demonstrate that integration of genomic analysis and gene expression profiling can identify genetic lesions undetected by routine methods and potential novel pathways involved in B-progenitor ALL pathogenesis.

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Section: Discussionmentioning

confidence: 94%

Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks

Bungaro

Dell’Orto

Zangrando

et al. 2008

Genes Chromosomes & Cancer

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“…These data were confirmed by quantitative PCR. The Notch-signaling cascade and its ligand JAG1 are involved in maintenance and renewal of hematopoietic stem cells and have been described as deregulated in various malignant hematopoietic disorders [41][42][43][44][45]. Stirewalt et al recently identified JAG1 expression changes in leukemic blasts compared with hematopoietic cells from healthy donors with subsequent confirmation of an increased expression of JAG1 using microarray data from 285 AML patients.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells

Stölzel

Steudel²,

Oelschlägel³

et al. 2010

Ann Hematol

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Treatment of acute myeloid leukemia (AML) remains challenging with many patients harboring unfavorable prognostic parameters such as FLT3 internal tandem duplication (FLT3-ITD) mutations leading to a constitutively activated FLT3-receptor tyrosine kinase (RTK). Activation of proteins by phosphorylation of tyrosine residues is a common mechanism in leukemia development. Therefore, specific tyrosine kinase inhibitors (TKI) have been developed for AML therapy and are currently under investigation. The staurosporine derivate PKC412 (Midostaurin) was found to be an effective inhibitor of the FLT3-RTK and is currently undergoing clinical trials for FLT3-mutated AML patients. Since resistance towards TKIs has been observed in vitro and in clinical trials, we have generated a PKC412-resistant clone (MV4-11r) of the human myelomonoblastic cell line MV4-11, which carries a homozygous FLT3-ITD mutation. MV4-11r displayed higher vitality after addition of PKC412 compared with MV4-11 with a pronounced reduction of apoptotic cells. Cytogenetic characterization revealed the acquisition of additional aberrations in the resistant cell line such as clonal alterations at chromosome 13q with additional FLT3 signals. Microarray analysis revealed significant expression changes in several genes prior to and after incubation with PKC412. The expression status of candidate genes being regulated by FLT-ITD like JAG1, p53, MCL-1, C-KIT, and FLT3/-L was confirmed by real-time PCR. In summary, resistance against PKC412 appears to be mediated by upregulation of anti-apoptotic genes and down-regulation of proapoptotic signals as well as genes that are involved in normal and malignant hematopoiesis.

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“…Overexpression of Jagged1, Jagged2, Notch1 and Notch2 proteins are found in samples of human multiple myeloma (15). Acute myelogenous leukemia (AML) is characterized by overexpression of Jagged1 mRNA/protein and Notch1 protein (16). Two recent studies have identified activating Notch1 mutations in chronic lymphocytic leukemia (CLL) (17,18).…”

Section: Notch Signaling Pathway Its Components and Their Role In Camentioning

confidence: 99%

Association between Notch signaling pathway and cancer

Lachej¹,

Didžiapetrienė²,

Kazbarienė³

et al. 2013

AML

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Background. The components of the Notch signaling pathway are important in maintaining the balance involved in cell proliferation, apoptosis and differentiation. Therefore, dysfunction of the Notch prevents differentiation, ultimately guiding undifferentiated cells toward malignant transformation. The aim of this article is to present recently published data concerning the role of the Notch signaling pathway components in development and prognosis of oncologic diseases, in occurrence of resistance to cytostatic agents and importance in creating of new cancer treatment approaches. Materials and methods. The Pubmed was the main source of looking for information for this article. Results. Recent investigations show that disorders of the Notch signaling pathway are associated with development of some human haematological and solid cancers. In different tissues and organs this active pathway can act as a tumor suppressor or an oncogene. Accordingly, the increased or decreased expression of its components is defined. Most of published data show that the increased expression of Notch pathway components correlates with a worse prognosis of cancer and a shorter survival. Recently, the Notch pathway has been reported to be involved in drug resistance. The modulation of the Notch signaling pathway could be helpful in treatment of some tumors with abnormal activity of this pathway’s components. Therefore changes in the expression of Notch components could become important predictive factors, helpful in selecting the proper treatment method. Conclusions. The results of recent studies are very important, since the detecting of the prognostic and predictive value of components of the Notch signaling pathway can allow creating new and improving already known methods of cancer diagnostic and treatment.

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A wide role for NOTCH1 signaling in acute leukemia

Cited by 68 publications

References 26 publications

Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks

Integration of genomic and gene expression data of childhood ALL without known aberrations identifies subgroups with specific genetic hallmarks

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells

Association between Notch signaling pathway and cancer

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