Current views on the role of Notch signaling and the pathogenesis of human leukemia
© Pancewicz and Nicot; licensee BioMed Central Ltd. 2011
Received: 21 April 2011
Accepted: 30 November 2011
Published: 30 November 2011
The Notch signaling pathway is highly conserved from Drosophila to humans and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis.
Constitutive activation of Notch signaling has been shown to result in excessive cellular proliferation and a wide range of malignancies, including leukemia, glioblastoma and lung and breast cancers. Notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. This minireview focuses on recent advances related to the mechanisms and roles of activated Notch1, Notch2, Notch3 and Notch4 signaling in human lymphocytic leukemia, myeloid leukemia and B cell lymphoma, as well as their significance, and recent advances in Notch-targeted therapies.
Canonical and noncanonical activation of the Notch signaling pathway
The Notch gene was first described following the observation of Notches on the wings of fruit flies (Drosophila melanogaster) caused by partial loss of function of the Notch gene. Notch signaling is involved in many biological processes, ranging from embryonic development to cell proliferation and survival. It has been demonstrated that the Notch signaling pathway is involved in vascular formation and morphogenesis during vascular development. Notch1, Notch2 and Notch4 and its ligands (Jagged1, Jagged2, Dll1 and Dll4) are expressed in vascular endothelium, whereas Notch3 is expressed in vascular smooth muscle cells. Mutations in Notch3 are associated with CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), the human degenerative vascular disease.
The role of the microenvironment in the activation of Notch in leukemia is increasingly recognized. Recently, cis-inhibition of Notch signaling by the DLL1 ligand has been described in Drosophila and mice . These investigations have suggested that while expression of ligands on neighboring cells stimulates Notch activation, expression on the same cell as the Notch receptor may have an inhibitory effect . Along these lines, activation of Notch signaling in B-cell malignancies might result from interactions between tumor cells as well as between the tumor cell and the microenvironment. There is evidence suggesting the importance of Notch signaling in the cross-talk between multiple myeloma (MM) cells and their environment. Bone marrow stromal cells express both Notch ligands, Jagged and δ, and are able to activate Notch signaling in MM cells [12, 13].
Mechanisms leading to constitutive activation of Notch signaling
Notch1 was discovered in humans through a t(7;9)(q34;q34.3) chromosomal translocation observed in some patients with T-cell acute lymphoblastic leukemia (T-ALL) [14, 15]. However, a direct role of Notch activation in T-ALL remained obscure, since only 1% to 3% of patients with T-ALL were found to carry this translocation. It was only after the discovery of a high rate of activating mutations that it became clear that Notch1 expression is linked to the development of T-ALL . Activating mutations identified in the T-ALL cluster at the heterodimerization domain (HD) and the proline, glutamine, serine and threonine (PEST) domain led to ligand-independent cleavage of the Notch receptor and a reduced degradation of NICD1, respectively. Recently, activating mutations in Notch were identified in more than 30% of human T-lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia (ATL) patients, suggesting an important role for Notch signaling in HTLV-I-associated ATL . Activating mutations found in ATL patients are different from those previously reported in patients with T-ALL and mostly involve single-substitution mutations in the PEST domain that do not create an early stop codon, but rather lead to reduced CDC4/Fbw7-mediated degradation and stabilization of NICD1 .
Additional mechanisms have also been reported to lead to increased Notch expression in cancer cells. Mutations and internal duplication insertions in exon 28 of NICD , as well as mutations in CDC4/Fbw7 [10, 19], have been reported, but they seem to occur at a very low frequency. The Wnt/β-catenin and Notch1 signaling pathways play an important role in a variety of biological processes, including cell proliferation and survival. Studies have shown that β-catenin can regulate the level and transcriptional activity of Notch1 . β-catenin can prevent NICD degradation, possibly by competing with CDC4/Fbw7-dependent degradation . Moreover, β-catenin increases the transcriptional activity of NICD, and the effects of β-catenin on Notch1 are noticeably reduced by overexpression of the lymphocyte enhancer-binding factor 1, LEF1.
Implication of Notch signaling in various hematological disorders
Mutation of Notch1 and Notch2 in human leukemia and/or lymphomaa
Increasing evidence suggests that Notch2 may play a role in leukemia and lymphoma. Early studies showed that feline leukemia virus recombinant genomes isolated from lymphomas captured Notch2, which included the intracellular ankyrin repeat functional domain in the envelope gene . Later it was found that Notch2 plays a role in CD8 thymocyte maturation and that enforced expression of activated Notch2 invariably resulted in T-cell leukemia in mice . Table 1 shows that approximately 8% of diffuse large B-cell lymphomas (DLBCLs) have Notch2 mutations . Similar to observations in Notch1, mutations in DLCBL affected the PEST domain or a single-amino acid substitution at the C terminus and resulted in Notch2-reduced turnover . These observations suggest Notch2 gain-of-function mutations in a subset of B-cell lymphomas. In fact, Notch2 is involved in the development of B1 and marginal zone B cells, and Notch2 is overexpressed in some marginal zone lymphomas (MZLs) . Potential activating mutations of human Notch2 presented in Table 1 were also detected in 5% of MZL patients . Notch2 may also play an indirect role in chronic B-cell lymphocytic leukemia (B-CLL) through upregulated expression of CD23 [33, 34].
A possible role of Notch3 in leukemia was postulated in studies in which transgenic mice expressing the constitutively active intracellular domain of Notch3 in thymocytes and T cells developed early and aggressive T-cell neoplasia . Importantly, these results were validated in humans, and examination of T-ALL patients demonstrated high expression of Notch3 and pTα transcripts, whereas the expression of these genes was considerably reduced in or absent from patients in remission . pTα and Notch3 interactions are essential for distribution of the E3 ligase protein, c-Cbl, to the lipid rafts. This is important in the development of leukemogenesis, since in the absence of pTα, c-Cbl targets Notch3 for proteasome degradation . Moreover, the NF-κΒ pathway may be involved in the development of Notch3-dependent T-cell lymphoma in humans, and there is genetic and biochemical evidence that Notch3 triggers multiple NF-κΒ activation pathways . Recently, Notch3 was found to control expression of mitogen-activated protein kinase phosphatase 1 and plays a role in the survival of T-ALL cells .
Notch4 is expressed in human bone marrow cells and in CD34+ and CD34- populations . Notch4 intracellular domain-transduced cord cells transplanted into mice showed remarkably elevated levels of engraftment of an immature T-cell population, while B-cell development was inhibited. Taken together, these results suggest that activation of Notch4 leads to enhanced stem cell activity, reduced differentiation and altered lymphoid development .
Clinical relevance and therapeutic approaches aimed at targeting Notch signaling
The molecular pathogenesis of Notch has recently been reviewed . Targeting Notch receptor cleavage through γ-secretase inhibitors (GSIs) is an attractive approach, as GSI treatment inhibits proliferation of T-ALL and ATL tumor cells in vitro and in vivo [42, 43]. The use of GSIs, however, poses several challenges. Current GSIs have been shown to have significant intestinal toxicity in patients because of the dual inhibition of Notch1 and Notch2. In addition, high levels of IL-6 and IL-8 have been reported to abrogate or significantly reduce the efficacy of the GSI (RO4929097) . GSIs may not be useful in patients with a Notch1 mutation in the HD, as this results in weakened association or complete dissociation of the receptor subunits and thus leads to ligand-independent activation. Finally, recent studies have also shown that T-ALL patients with loss of PTEN are resistant to GSI effects . Together these results highlight the need for new targeted therapies.
Recently, the use of therapeutic antibodies that selectively block Notch1 receptor signaling has been reported to inhibit tumor growth in mouse models . Rather than targeting receptor processing, alternative strategies may also focus on blocking NICD functions and transcriptional activities. Along these lines, the use of a stapled peptide to inhibit the Notch transcription factor complex has been reported to result in Notch-specific antiproliferative effects in cultured cells and in a mouse model of Notch1-driven T-ALL .
Increased Notch signaling is linked to hematological malignancies. Overexpression of activated the Notch1, Notch2 or Notch3 genes in bone marrow progenitor cells reliably induces T-ALL at high frequency in murine models. Activating mutations in Notch1 is frequent in both T-ALL and ATL. It has been proposed that a fraction of T-ALLs that present as leukemia without evidence of thymic involvement may originate from bone marrow progenitors that have acquired a Notch1 mutation, suggesting that constitutive active Notch1 could, in some cases, be an initial event driving tumor development. On the other hand, animal model studies have indicated that Notch can also play a secondary role during T-ALL development. The role played by Notch1 in other human leukemias is less clear, as is the potential role of other Notch genes. Although inhibition of Notch signaling in xenograft tumors in animal models effectively prevents tumor cell growth, clinical outcomes in humans do not seem to be significantly associated with Notch status, which has an impact on early response to treatment but not on general outcomes in pediatric patients with T-ALL . This may be related to acquisition of additional mutations in patients who have received several therapies and may relieve tumor cells from Notch1 addiction. As is the case with many targeted therapies, resistance to single drugs emerges rapidly, suggesting that a multidrug chemotherapy targeting Notch and connected pathways is needed.
nuclear factor κΒ.
This work was supported by National Cancer Institute (NCI) grant CA106258 (to CN). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI. The authors thank Brandi Miller for editorial assistance.
- D'Souza B, Meloty-Kapella L, Weinmaster G: Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010, 92: 73-129.View ArticlePubMedPubMed CentralGoogle Scholar
- Kovall RA, Blacklow SC: Mechanistic insights into Notch receptor signaling from structural and biochemical studies. Curr Top Dev Biol. 2010, 92: 31-71.View ArticlePubMedGoogle Scholar
- Kopan R, Ilagan MXG: The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009, 137: 216-233. 10.1016/j.cell.2009.03.045.View ArticlePubMedPubMed CentralGoogle Scholar
- Bray S, Bernard F: Notch targets and their regulation. Curr Top Dev Biol. 2010, 92: 253-275.View ArticlePubMedGoogle Scholar
- Fortini ME: Notch signaling: the core pathway and its posttranslational regulation. Dev Cell. 2009, 16: 633-647. 10.1016/j.devcel.2009.03.010.View ArticlePubMedGoogle Scholar
- Chastagner P, Israël A, Brou C: AIP4/Itch regulates Notch receptor degradation in the absence of ligand. PLoS One. 2008, 3: e2735-10.1371/journal.pone.0002735.View ArticlePubMedPubMed CentralGoogle Scholar
- Wilkin MB, Carbery AM, Fostier M, Aslam H, Mazaleyrat SL, Higgs J, Myat A, Evans DAP, Cornell M, Baron M: Regulation of Notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol. 2004, 14: 2237-2244. 10.1016/j.cub.2004.11.030.View ArticlePubMedGoogle Scholar
- McGill MA, McGlade CJ: Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem. 2003, 278: 23196-23203. 10.1074/jbc.M302827200.View ArticlePubMedGoogle Scholar
- Fortini ME, Bilder D: Endocytic regulation of Notch signaling. Curr Opin Genet Dev. 2009, 19: 323-328. 10.1016/j.gde.2009.04.005.View ArticlePubMedPubMed CentralGoogle Scholar
- Welcker M, Clurman BE: FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008, 8: 83-93. 10.1038/nrc2290.View ArticlePubMedGoogle Scholar
- del Álamo D, Rouault H, Schweisguth F: Mechanism and significance of cis-inhibition in Notch signalling. Curr Biol. 2011, 21: R40-R47. 10.1016/j.cub.2010.10.034.View ArticlePubMedGoogle Scholar
- Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT: Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003, 425: 841-846. 10.1038/nature02040.View ArticlePubMedGoogle Scholar
- Maillard I, Adler SH, Pear WS: Notch and the immune system. Immunity. 2003, 19: 781-791. 10.1016/S1074-7613(03)00325-X.View ArticlePubMedGoogle Scholar
- Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, Sklar J: TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991, 66: 649-661. 10.1016/0092-8674(91)90111-B.View ArticlePubMedGoogle Scholar
- Reynolds TC, Smith SD, Sklar J: Analysis of DNA surrounding the breakpoints of chromosomal translocations involving the β T cell receptor gene in human lymphoblastic neoplasms. Cell. 1987, 50: 107-117. 10.1016/0092-8674(87)90667-2.View ArticlePubMedGoogle Scholar
- Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC: Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004, 306: 269-271. 10.1126/science.1102160.View ArticlePubMedGoogle Scholar
- Pancewicz J, Taylor JM, Datta A, Baydoun HH, Waldmann TA, Hermine O, Nicot C: Notch signaling contributes to proliferation and tumor formation of human T-cell leukemia virus type 1-associated adult T-cell leukemia. Proc Natl Acad Sci USA. 2010, 107: 16619-16624. 10.1073/pnas.1010722107.View ArticlePubMedPubMed CentralGoogle Scholar
- Sulis ML, Williams O, Palomero T, Tosello V, Pallikuppam S, Real PJ, Barnes K, Zuurbier L, Meijerink JP, Ferrando AA: NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood. 2008, 112: 733-740. 10.1182/blood-2007-12-130096.View ArticlePubMedPubMed CentralGoogle Scholar
- O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, Hardwick J, Welcker M, Meijerink JP, Pieters R, Draetta G, Sears R, Clurman BE, Look AT: FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors. J Exp Med. 2007, 204: 1813-1824. 10.1084/jem.20070876.View ArticlePubMedPubMed CentralGoogle Scholar
- Jin YH, Kim H, Ki H, Yang I, Yang N, Lee KY, Kim N, Park HS, Kim K: β-catenin modulates the level and transcriptional activity of Notch1/NICD through its direct interaction. Biochim Biophys Acta. 2009, 1793: 290-299. 10.1016/j.bbamcr.2008.10.002.View ArticlePubMedGoogle Scholar
- Erbilgin Y, Sayitoglu M, Hatirnaz O, Dogru O, Akcay A, Tuysuz G, Celkan T, Aydogan G, Salcioglu Z, Timur C, Yuksel-Soycan L, Ure U, Anak S, Agaoglu L, Devecioglu O, Yildiz I, Ozbek U: Prognostic significance of NOTCH1 and FBXW7 mutations in pediatric T-ALL. Dis Markers. 2010, 28: 353-360.View ArticlePubMedPubMed CentralGoogle Scholar
- Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K, Allen CG, Gale RE, Buck G, Richards S, Paietta E, Rowe JM, Tallman MS, Goldstone AH, Ferrando AA, Linch DC: Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol. 2009, 27: 4352-4356. 10.1200/JCO.2009.22.0996.View ArticlePubMedPubMed CentralGoogle Scholar
- Allenspach EJ, Maillard I, Aster JC, Pear WS: Notch signaling in cancer. Cancer Biol Ther. 2002, 1: 466-476. 10.4161/cbt.1.5.162.View ArticlePubMedGoogle Scholar
- Paganin M, Ferrando A: Molecular pathogenesis and targeted therapies for NOTCH1-induced T-cell acute lymphoblastic leukemia. Blood Rev. 2011, 25: 83-90. 10.1016/j.blre.2010.09.004.View ArticlePubMedGoogle Scholar
- Zweidler-McKay PA: Notch signaling in pediatric malignancies. Curr Oncol Rep. 2008, 10: 459-468. 10.1007/s11912-008-0071-2.View ArticlePubMedGoogle Scholar
- Radtke F, Fasnacht N, MacDonald HR: Notch signaling in the immune system. Immunity. 2010, 32: 14-27. 10.1016/j.immuni.2010.01.004.View ArticlePubMedGoogle Scholar
- Mansour MR, Duke V, Foroni L, Patel B, Allen CG, Ancliff PJ, Gale RE, Linch DC: Notch-1 mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia. Clin Cancer Res. 2007, 13: 6964-6969. 10.1158/1078-0432.CCR-07-1474.View ArticlePubMedGoogle Scholar
- Eguchi-Ishimae M, Eguchi M, Kempski H, Greaves M: NOTCH1 mutation can be an early, prenatal genetic event in T-ALL. Blood. 2008, 111: 376-378. 10.1182/blood-2007-02-074690.View ArticlePubMedGoogle Scholar
- Rohn JL, Lauring AS, Linenberger ML, Overbaugh J: Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma. J Virol. 1996, 70: 8071-8080.PubMedPubMed CentralGoogle Scholar
- Witt CM, Hurez V, Swindle CS, Hamada Y, Klug CA: Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells. Mol Cell Biol. 2003, 23: 8637-8650. 10.1128/MCB.23.23.8637-8650.2003.View ArticlePubMedGoogle Scholar
- Lee S, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S: Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci. 2009, 100: 920-926. 10.1111/j.1349-7006.2009.01130.x.View ArticlePubMedGoogle Scholar
- Trøen G, Wlodarska I, Warsame A, Hernández Llodrà S, De Wolf-Peeters C, Delabie J: NOTCH2 mutations in marginal zone lymphoma. Haematologica. 2008, 93: 1107-1109. 10.3324/haematol.11635.View ArticlePubMedGoogle Scholar
- Hubmann R, Düchler M, Schnabl S, Hilgarth M, Demirtas D, Mitteregger D, Hölbl A, Vanura K, Le T, Look T, Schwarzmeier JD, Valent P, Jäger U, Shehata M: NOTCH2 links protein kinase C δ to the expression of CD23 in chronic lymphocytic leukaemia (CLL) cells. Br J Haematol. 2010, 148: 868-878. 10.1111/j.1365-2141.2009.08024.x.View ArticlePubMedGoogle Scholar
- Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R: Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood. 2002, 99: 3742-3747. 10.1182/blood.V99.10.3742.View ArticlePubMedGoogle Scholar
- Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, Lendahl U, Fehling HJ, Hayday AC, Frati L, von Boehmer H, Gulino A, Screpanti I: Combined expression of pTα and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci USA. 2002, 99: 3788-3793. 10.1073/pnas.062050599.View ArticlePubMedPubMed CentralGoogle Scholar
- Asnafi V, Beldjord K, Boulanger E, Comba B, Le Tutour P, Estienne MH, Davi F, Landman-Parker J, Quartier P, Buzyn A, Delabesse E, Valensi F, Macintyre E: Analysis of TCR, pTα, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment. Blood. 2003, 101: 2693-2703. 10.1182/blood-2002-08-2438.View ArticlePubMedGoogle Scholar
- Checquolo S, Palermo R, Cialfi S, Ferrara G, Oliviero C, Talora C, Bellavia D, Giovenco A, Grazioli P, Frati L, Gulino A, Screpanti I: Differential subcellular localization regulates c-Cbl E3 ligase activity upon Notch3 protein in T-cell leukemia. Oncogene. 2010, 29: 1463-1474. 10.1038/onc.2009.446.View ArticlePubMedGoogle Scholar
- Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A, Screpanti I: Constitutive activation of NF-κΒ and T-cell leukemia/lymphoma in Notch3 transgenic mice. EMBO J. 2000, 19: 3337-3348. 10.1093/emboj/19.13.3337.View ArticlePubMedPubMed CentralGoogle Scholar
- Masiero M, Minuzzo S, Pusceddu I, Moserle L, Persano L, Agnusdei V, Tosello V, Basso G, Amadori A, Indraccolo S: Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. Leukemia. 2011, 25: 588-598. 10.1038/leu.2010.323.View ArticlePubMedGoogle Scholar
- Karanu FN, Yuefei L, Gallacher L, Sakano S, Bhatia M: Differential response of primitive human. Leukemia. 2003, 17: 1366-1374. 10.1038/sj.leu.2402973.View ArticlePubMedGoogle Scholar
- Vercauteren SM, Sutherland HJ: Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood. 2004, 104: 2315-2322. 10.1182/blood-2004-01-0204.View ArticlePubMedGoogle Scholar
- Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, Tsaparikos K, Jani JP, Hosea N, Sands M, Randolph S, Smeal T: Evaluation of selective γ-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010, 9: 1618-1628. 10.1158/1535-7163.MCT-10-0034.View ArticlePubMedGoogle Scholar
- Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H, Linn M, Flohr A, Jakob-Røtne R, Jacobsen H, Glenn K, Heimbrook D, Boylan JF: Preclinical profile of a potent γ-secretase inhibitor targeting Notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009, 69: 7672-7680. 10.1158/0008-5472.CAN-09-1843.View ArticlePubMedGoogle Scholar
- He W, Luistro L, Carvajal D, Smith M, Nevins T, Yin X, Cai J, Higgins B, Kolinsky K, Rizzo C, Packman K, Heimbrook D, Boylan JF: High tumor levels of IL6 and IL8 abrogate preclinical efficacy of the γ-secretase inhibitor, RO4929097. Mol Oncol. 2011, 5: 292-301. 10.1016/j.molonc.2011.01.001.View ArticlePubMedGoogle Scholar
- Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zúñiga-Pflücker JC, Dominguez M, Ferrando AA: Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007, 13: 1203-1210. 10.1038/nm1636.View ArticlePubMedPubMed CentralGoogle Scholar
- Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW: Therapeutic antibody targeting of individual Notch receptors. Nature. 2010, 464: 1052-1057. 10.1038/nature08878.View ArticlePubMedGoogle Scholar
- Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE: Direct inhibition of the NOTCH transcription factor complex. Nature. 2009, 462: 182-188. 10.1038/nature08543.View ArticlePubMedPubMed CentralGoogle Scholar
- Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, Kaltenbach S, Yakouben K, Mazingue F, Robert A, Boutard P, Plantaz D, Rohrlich P, van Vlierberghe P, Preudhomme C, Otten J, Speleman F, Dastugue N, Suciu S, Benoit Y, Bertrand Y, Cavé H, EORTC-CLG: NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010, 24: 2023-2031. 10.1038/leu.2010.205.View ArticlePubMedGoogle Scholar
- Park MJ, Taki T, Oda M, Watanabe T, Yumura-Yagi K, Kobayashi R, Suzuki N, Hara J, Horibe K, Hayashi Y: FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol. 2009, 145: 198-206. 10.1111/j.1365-2141.2009.07607.x.View ArticlePubMedGoogle Scholar
- Sportoletti P, Baldoni S, Cavalli L, Del Papa B, Bonifacio E, Ciurnelli R, Bell AS, Di Tommaso A, Rosati E, Crescenzi B, Mecucci C, Screpanti I, Marconi P, Martelli MF, Di Iannini M, Falzetti F: NOTCH1 PEST domain mutation is an adverse prognostic factor in B-CLL. Br J Haematol. 2010, 151: 404-406. 10.1111/j.1365-2141.2010.08368.x.View ArticlePubMedGoogle Scholar
- Di Ianni M, Baldoni S, Rosati E, Ciurnelli R, Cavalli L, Martelli MF, Marconi P, Screpanti I, Falzetti F: A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol. 2009, 146: 689-691. 10.1111/j.1365-2141.2009.07816.x.View ArticlePubMedGoogle Scholar
- Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, Escaramis G, Jares P, Beà S, González-Díaz M, Bassaganyas L, Baumann T, Juan M, López-Guerra M, Colomer D, Tubío JM, López C, Navarro A, Tornador C, Aymerich M, Rozman M, Hernández JM, Puente DA, Freije JM, Velasco G, Gutiérrez-Fernández A, Costa D, Carrió A, Guijarro S, Enjuanes A, et al: Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011, 475: 101-105. 10.1038/nature10113.View ArticlePubMedPubMed CentralGoogle Scholar
- Fu L, Kogoshi H, Nara N, Tohda S: NOTCH1 mutations are rare in acute myeloid leukemia. Leuk Lymphoma. 2006, 47: 2400-2403. 10.1080/10428190600773339.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/502/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.