Sage Journals: Discover world-class research

Abstract

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti-NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus.

Keywords

T-ALL NOTCH1 gamma-secretase inhibitor

Clinical challenges and molecular features of T-ALL

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive hematologic tumor that generally affects children and adolescents but also arises in adults. T-ALL accounts for 10–15% of pediatric and 25% of adult ALL cases [Ferrando et al. 2002] and is characteristically more prevalent in males than in females (male-to-female ratio 3:1). Patients presenting with diffuse (>25%) bone marrow infiltration are diagnosed with T-cell acute lymphoblastic leukemia, while those with mediastinal masses and limited or no bone marrow involvement are diagnosed as T-cell acute lymphoblastic lymphoma. T-ALL was originally associated with very poor prognosis. However, the introduction of intensified chemotherapy protocols have resulted in marked improvements in the clinical outcome of this disease over the last decades. Current long-term survival rates in T-ALL are about 75–85% in children and adolescents and about 40–50% in adults [Pui et al. 2008]. Despite this progress, the outcome of T-ALL patients with primary resistant or relapsed disease remains very poor [Oudot et al. 2008].

T-cell transformation is a multistep process resulting from the accumulation of genetic alterations in oncogenes and tumor suppressor genes, which together disrupt key pathways responsible for the control of cell growth, proliferation survival in normal T-cell progenitors. The most frequent of these genetic lesions in pediatric T-ALL is the deletion of the CDKN2A locus in chromosome 9p22 present in up to 70% of cases. CDKN2A comprises the p14/INK4A and 16/ARF tumor suppressor genes which control cell cycle regulation and P53-mediated apoptosis, respectively [Ferrando et al. 2002; Hebert et al. 1994]. Moreover, over 60% of T-ALL cases show aberrant activation of the NOTCH1 signaling pathway making NOTCH1 the most prevalent oncogene in this disease [Weng et al. 2004]. In addition, about 40% of T-ALLs harbor chromosomal translocations juxtaposing developmentally important transcription factor oncogenes next to strong regulatory elements located in the vicinity of the T-cell receptor β (TCRB) gene in chromosome 7q34 or the T-cell receptor α-δ (TCRAD) locus in chromosome 14q11 [Ferrando and Look, 2000]. These T-ALL-specific transcription factor oncogenes include basic helix–loop–helix (bHLH) family members such as TAL1 [Begley et al. 1989; Bernard et al. 1990; Chen et al. 1990; Finger et al. 1989], TAL2 [Xia et al. 1991], LYL1 [Mellentin et al. 1989] and BHLHB1 [Wang et al. 2000]; LIM-only domain (LMO) proteins such as LMO1 and LMO2 [Boehm et al.; Greenberg et al. 1990; McGuire et al. 1989; Royer-Pokora et al. 1991; Warren et al. 1994]; the TLX1/HOX11 [Dube et al. 1991; Hatano et al. 1991; Kennedy et al. 1991] TLX3/HOX11L2, [Hansen-Hagge et al. 2002]; NKX2.5 [Nagel et al. 2003; Przybylski et al. 2006]; and HOXA homeobox genes [Hansen-Hagge et al. 2002; Soulier et al. 2005]; the MYC [Erikson et al. 1986; Inaba et al. 1990; Shima-Rich et al. 1997; Shima et al. 1986; Urashima et al. 1992] and MYB [Clappier et al. 2007] oncogenes; and TAN1, a truncated and constitutively activated form of the NOTCH1 receptor [Ellisen et al. 1991; Palomero et al. 2006a]. In some cases, these factors can also be activated in the context of other non-TCR-associated chromosomal abnormalities. This is the case for small deletions activating TAL1 [Aplan et al. 1990] and LMO2 [Van Vlierberghe et al. 2006], duplications of the MYB oncogene [Clappier et al. 2007; Lahortiga et al. 2007; O’Neil et al. 2007b] and the t(5;14)(q32;q11) translocation which activates the TLX3 oncogene in chromosome 5 by relocating it to the vicinity of the BCL11B locus in chromosome 14 [Nagel et al. 2007; Su et al. 2006]. Finally, about 10% of T-ALL cases harbor translocations resulting in the expression of fusion transcripts encoding chimerical transcription factor oncogenes. These include PICALMMLLT10/CALM-AF10 [Asnafi et al. 2003; Carlson et al. 2000; Dreyling et al. 1996], MLL-MLLT1/MLL-ENL [Chervinsky et al. 1995; Rubnitz et al. 1996] SET-NUP214 [Van Vlierberghe et al. 2008], NUP98-RAP1GSD1 [Hussey et al. 1999; Mecucci et al. 2000]. More recently, a series of loss of function mutations and deletions have been described for transcription factor tumor suppressor genes, such as WT1 [Tosello et al. 2009] [Renneville et al. 2010], LEF1 [Gutierrez et al. 2010], PHF6 [Van Vlierberghe et al., 2010], BCL11B [De Keersmaecker et al. 2010]; RUNX1 [Della Gatta et al. 2012; Grossmann et al. 2011; Zhang et al. 2012] and ETV6 [Gutierrez et al. 2010; Van Vlierberghe et al., 2011]. In addition, genetic alterations in signal transduction pathways can also contribute to the pathogenesis of T-ALL. These include deletions and mutations in PTEN [Palomero et al. 2007], ABL1 fusion oncogenes (NUP214-ABL1, EML1-ABL1 and ETV6-ABL1) [De Keersmaecker et al. 2005; Graux et al. 2004]; mutations activating the RAS signaling pathway [Balgobind et al. 2008; Bar-Eli et al. 1989; Campbell and Der, 2004], activating mutations in JAK1 and JAK3 [Flex et al. 2008; Zhang et al. 2012], activating mutations in IL7R [Zenatti et al. 2011; Zhang et al. 2012], FLT3 mutations [Paietta et al. 2004], PTPN2 deletions [Kleppe et al. 2011] and IRS4 translocations [Karrman et al. 2009]. Finally, deletions and loss of function mutations in histone-modifying genes such as SUZ12, EED, EZH2, and SETD2 have been found in T-ALL, which highlight the role of altered epigenetic regulation in T-cell transformation [Ntziachristos et al. 2012; Zhang et al. 2012].

The NOTCH1 signaling pathway

NOTCH signaling is a highly evolutionary conserved pathway responsible for the direct transduction of developmental signals at the cell surface into changes in gene expression in the nucleus. The NOTCH family of receptors is composed of four highly related proteins (NOTCH1–4). NOTCH receptors are heterodimeric transmembrane proteins composed of an extracellular subunit and a transmembrane and intracellular subunit, which interact via a specialized heterodimerization domain (HD). The extracellular subunit of NOTCH1 contains several EGF-like repeats involved in ligand-receptor interaction and three LIN-12/NOTCH repeats (LNRs), which stabilize the dimerization domain by holding the two NOTCH subunits together. The transmembrane-intracellular subunit of the receptor is composed of a short extracellular juxtamembrane peptide followed by a transmembrane sequence and a series of cytoplasmatic domain including RAM domain, nuclear localization signals (NLS), a series of ankyrin repeats, a region rich in glutamine (OPA), and a C-terminal PEST domain, which together function as a ligand-activated transcription factor [Aster et al. 2008]. Upon interaction with its ligands (Delta-like 1, 3 and 4; and Jagged 1 and 2), NOTCH1 undergoes a conformational change in the LNR–HD complex, which results in the proteolytic cleavage of the transmembrane-intracellular domain of the receptor, first by an ADAM metalloprotease, and subsequently by the γ-secretase complex [Brou et al. 2000; Mumm and Kopan, 2000]. This final cleavage releases the intracellular domains of NOTCH1 (ICN1) from the membrane, allowing its translocation to the nucleus where it activates gene expression via association with the RBPJ DNA binding protein and members of the mastermind-like family of coactivators [Fryer et al. 2002; Lubman et al. 2007]. Finally, activated NOTCH1 is quickly targeted for proteasomal degradation by FBXW7, an E3 ubiquitin ligase that recognize the PEST domain of ICN1 and mediates the termination of NOTCH1 signaling in the nucleus [Hubbard et al. 1997; Sundaram and Greenwald, 1993].

NOTCH1 signaling in normal T-cell development

In the hematopoietic system, NOTCH1 is strictly required for the commitment of multipotent hematopoietic progenitors to the T-cell lineage and to support cell growth, proliferation and survival at multiple stages of thymocyte development [Hozumi et al. 2008; Tanigaki and Honjo, 2007]. Indeed, conditional inactivation of RBPJ in T-cells results in the blockage of T development and in ectopic B-cell development in the thymus [Han et al. 2002; Radtke et al. 1999]. These results suggest that Notch provides a key regulatory signal in determining T lymphoid versus B lymphoid cell fate, In addition, NOTCH1 is involved in the progression through the early DN1, DN2 and DN3 stages of thymocyte development [Schmitt et al. 2004] and in the regulation of TCRB rearrangement [Wolfer et al. 2002].

NOTCH1 signaling in T-ALL

The first indication that Notch signaling could be an important element in leukemogenesis came in the early 1990s when Ellisen and colleagues identified a rare chromosomal translocation t(7;9)(q34;q34.3) involving the human NOTCH1 gene in T-ALL [Ellisen et al. 1991]. However, the prominent role of NOTCH1 signaling in the pathogenesis of T-ALL was only realized in 2004 with the identification of activating NOTCH1 mutations in over 60% of T-ALLs [Weng et al. 2004]. NOTCH1 mutations localized in the HD domain found in 20% of T-ALLs result in ligand-independent activation of the receptor, while mutations of the PEST domain present in 15% of T-ALLs cause increased ICN1 stability and aberrantly prolonged NOTCH1 activation [Weng et al. 2004]. In addition, juxtamembrane expansion (JME) alleles [Sulis et al. 2008] and intragenic deletions encompassing the 5’ region of the NOTCH1 locus (NOTCH1 del-N) [Haydu et al. 2012] result in very high levels of NOTCH1 signaling in rare cases of T-ALL. Finally, 20% of T-ALL cases show activation of NOTCH1 via mutations in the FBXW7 gene [Malyukova et al. 2007; O’Neil et al. 2007a; Thompson et al. 2007]. Mechanistically, FBXW7 mutations are related to NOTCH1 PEST mutations as they result in increased ICN1 protein stability. However, FBXW7 mutations may also be associated with additional oncogenic functions as this F-box protein is also involved in the degradation of other important oncoproteins such as MYC, JUN, MCL1, and Cyclin E [Clurman et al. 1996; Inuzuka et al. 2011; Sugimoto and Himeno, 1992; Tan et al. 2008; Wei et al. 2005]. Notably, in about 25% of T-ALL cases HD mutations are associated with PEST or FBXW7 mutations which results in a dual NOTCH1 activation that combines ligand-independent activation and prolonged ICN1 stability [Weng et al. 2004].

Genes and pathways deregulated by activated NOTCH1 in T-ALL

Recent progress in the identification of the transcriptional regulatory networks that control T-cell transformation downstream of NOTCH1 has shown a close relationship between oncogenic NOTCH1 signaling and the transcriptional control of cell growth and metabolism. Thus, NOTCH1 directly controls multiple genes involved in anabolic pathways and further promotes cell growth via direct transcriptional upregulation of MYC [Palomero et al. 2006c; Sharma et al. 2006; Weng et al. 2006]. The positive effects of activated NOTCH1 in cell growth are further sustained by interaction of NOTCH1 signaling with the PI3K–AKT–mTOR pathway [Chan et al. 2007; Ciofani and Zuniga-Pflucker, 2005; Palomero et al. 2007]. In addition, NOTCH1 transcriptionally upregulates molecules upstream of the PI3K such as interleukin 7 receptor alpha chain (IL7RA), the pre-T-cell receptor alpha (PTCRA) and the insulin-like growth factor 1 receptor (IGF1R) [Gonzalez-Garcia et al. 2009; Medyouf et al. 2011; Reizis and Leder, 2002].

Another important mechanism in T-cell transformation downstream of oncogenic NOTCH is the promotion of the G1/S cell cycle progression mediated by direct and indirect regulation of cell cycle regulator genes. NOTCH1 signaling promotes G1/S cell cycle progression via upregulation of CDK4 and CDK6 [Joshi et al. 2009] and downregulation of p27/KIP1 and p18/INK4C cell cycle inhibitors [Dohda et al. 2007; Palomero et al. 2006c].

Although the role and mechanisms of NOTCH1 signaling in promoting increased survival in T-ALL are less well characterized, constitutively active NOTCH1 can activate the NF-kappaB signaling supporting a major role for NF-kappaB in NOTCH1 induced T-cell transformation [Vilimas et al. 2007]. Consistently, HES1, a transcriptional repressor downstream of NOTCH1, sustains IKK activation in T-ALL by repressing the CYLD deubiquitinase [Espinosa et al. 2010].

NOTCH1 contributes to the control of epigenetic modulators of gene expression as demonstrated by the loss of the repressive mark Lys27 trimethylation of histone 3 in NOTCH1 target genes [Ntziachristos et al. 2012]. Thus, NOTCH1 antagonizes the function of the Polycomb repressive complex 2 (PRC2), responsible for writing the H3K27 mark [Ntziachristos et al. 2012]. Moreover, mutational loss of key components of the pRC2 complex such as EZH2, SUZ12, and EED are frequently found in T-ALL [Ntziachristos et al. 2012; Zhang et al. 2012].

Finally, an emerging and still developing concept is the role of microRNA regulation in NOTCH1 induced T-ALL. In this regard, expression of miR19 can accelerate the development of NOTCH1-induced T-ALL in mice [Mavrakis et al. 2010]. Moreover, the identification of a T-ALL patient with dual translocations activating the 17-92 cluster, where miR-19 is located, and NOTCH1 indicate the relevance of this interaction in T-cell transformation [Mavrakis et al. 2010]. In addition, NOTCH1 signaling downregulates miR-451 and miR-709 in mouse NOTCH1-induced leukemias by inducing degradation of the E2A tumor suppressor [Li et al. 2011].

Clinical impact of aberrant NOTCH1 signaling in T-ALL

Given the high prevalence of activating NOTCH1 mutations in T-ALL, a number of groups have analyzed the possible association of NOTCH1 activation with clinical outcome in this disease. By analyzing the effects of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 pediatric patients with T-ALL enrolled in the ALL-Berlin–Frankfurt–Munster (BFM) 2000 study, Breit and coworkers originally showed that the presence of NOTCH1 mutations was significantly correlated with a good prednisone response, favorable minimal residual disease kinetics and improved long-term outcome in children with T-ALL [Breit et al. 2006]. Similarly, analysis of the prognostic impact of both NOTCH1 and FBXW7 mutations in 55 pediatric T-ALL patients treated on the Japan Association of Childhood Leukaemia Study (JACLS) protocols ALL-97 show a favorable prognosis for pediatric T-ALL patients carrying NOTCH1 or a FBXW7 mutation [Park et al. 2009]. A similar result was obtained in the analysis of 141 adult T-ALL patients treated in either the Lymphoblastic Acute Leukemia in Adults 94 (LALA-94) (n = 87) and GRAALL-2003 (n = 54) trials, in which NOTCH1 or FBXW7 mutations correlated with favorable outcome [Asnafi et al. 2009]. However, analysis of a series of T-ALL patients treated on the United Kingdom Acute Lymphoblastic Leukaemia XII (UKALLXII)/Eastern Cooperative Oncology Group (ECOG) E2993 protocol found no significant association between NOTCH1 and FBXW7 mutations and prognosis [Mansour et al. 2009]. Similarly, while NOTCH1 and FBXW7 mutations are associated with favorable early response to treatment in pediatric T-ALL, this early advantage did not ultimately translate to long-term outcome in DCOG or COALL protocols and in the EORTC 58881 and 58951 clinical trials [Clappier et al. 2010; Zuurbier et al. 2010]. Interestingly, the favorable prognosis of NOTCH1/FBXW7 mutations in adult T-ALL is found in more intense, pediatric-inspired GRAALL chemotherapy protocols but not in the less-intense LALA-94 study [Ben Abdelali et al. 2011], suggesting that differences in therapy intensification may influence the prognostic impact of NOTCH activating mutations in T-ALL.

Gamma secretase inhibitors, an emerging targeted therapy for T-ALL

The high prevalence of NOTCH1 mutations and the central role of NOTCH signaling in T-ALL make of NOTCH1 a potentially important therapeutic target in this disease. Much of the current effort targeting NOTCH1 in T-ALL aims to block NOTCH signaling with small molecule inhibitors of the γ-secretase complex. Indeed a number of γ-secretase inhibitors (GSI) originally developed for the treatment of Alzheimer’s disease is already in clinical development. GSIs reduce levels of intracellular NOTCH1 and transcriptional down regulation of NOTCH1-target genes in T-ALL [Palomero et al. 2006c]. Proof of principle for the antileukemic effects of GSIs was shown by the ability of compound E, a highly specific GSI to block NOTCH1 signaling and induce cell cycle arrest and decreased proliferation in T-ALL cell lines [Palomero et al. 2006b; Weng et al. 2004]. In addition, GSI treatment of mouse models of T-ALL showed marked antileukemic effects in vivo [Cullion et al. 2009; Tatarek et al. 2011]. Still, to date, only one clinical trial using GSIs in T-ALL has been reported [Deangelo et al. 2006]. This phase I study tested MK-0752, an oral GSI developed by Merck in seven patients with T-ALL. One patient with a NOTCH1 mutated T-ALL achieved a 45% reduction in a mediastinal mass after 28 days of treatment. However, this patient subsequently progressed and overall no patient achieved an objective durable response to treatment. In addition, most patients in the study showed dose-limiting gastrointestinal toxicity. The toxic effects of GSIs are an on target side effect resulting from the inhibition of NOTCH1 and NOTCH2 in intestinal progenitor cells [Riccio et al. 2008]. NOTCH1 and NOTCH2 play an important role in the specification of absorptive cell fate in intestinal stem cells. As a result, genetic and pharmacologic inhibition of NOTCH1 and NOTCH2 signals results in intestinal secretory cell metaplasia with accumulation of mucus-secreting goblet cells and malabsorption [Riccio et al. 2008; van Es et al. 2005]. Thus, overcoming GSI-induced gut toxicity has become a major imperative for the clinical development of GSIs. In this regard, the use of parenteral formulations and intermittent dosing schedules has been proposed as possible approaches to ameliorate the toxic effects of GSIs. Notably, inhibition of NOTCH signaling with GSIs can reverse glucocorticoid resistance in T-ALL and abrogate the gastrointestinal toxicity induced by GSIs in animal models [Real and Ferrando, 2009; Real et al. 2009; Samon et al. 2012; Wei et al. 2010]. The synergistic effects of GSI and glucocorticoids and the enteroprotective effects of dexamethosone against GSI-induced gut toxicity warrant the design of clinical trials testing the safety and efficacy of this drug combination in T-ALL [Cullion et al. 2009; Tammam et al. 2009; Wei et al. 2010]. Alternatively, combination therapies of GSIs with chemotherapy or other molecularly target agents could increase the antileukemic effects of these drugs facilitating the use of decreased GSI dosing with reduced GSI-induced gut toxicity. Combination treatment of GSIs with drugs targeting NFkB signaling [Vilimas et al. 2007], CDK inhibitors [Rao et al. 2009], PI3K–AKT–mTOR inhibitors [Chan et al. 2007; Cullion et al. 2009; Palomero et al. 2007; Sanda et al. 2010], and HDAC inhibitors [Sanda et al. 2010] have been proposed.

Finally, early observations of in vitro resistance to GSI treatment suggest that T-ALL cells can become resistance to NOTCH inhibition. Notably, PTEN loss and consequent constitutive activation of the PI3K–AKT pathway is present in 17% of primary T-ALL samples at diagnosis and can drive resistance to GSI treatment in T-ALL cell lines [Palomero et al. 2007]. In addition, FBXW7 mutations are also more prevalent in GSI-resistant T-ALL cell lines, compared with GSI-sensitive tumors [O’Neil et al. 2007a; Thompson et al. 2007]. However, additional T-ALL cooperating mutations may be needed to confer full resistance to NOTCH inhibition [Medyouf et al. 2010].

Novel approaches for NOTCH1 inhibition

Specific antibodies directed against individual NOTCH proteins can selectively block the activities of different NOTCH receptors [Aste-Amezaga et al. 2010; Li et al. 2008; Wu et al. 2010]. Anti-NOTCH1 antibodies recognizing the HD LNR repeat region of the receptor can effectively inhibit the activity of wild-type NOTCH1 and leukemia associated NOTCH1 mutants and effectively block tumor growth in vitro and in vivo [Aste-Amezaga et al. 2010; Wuet al. 2010]. Inhibition of ADAM10 may also facilitate effective inhibition of wild-type and mutant NOTCH receptors [Sulis et al. 2011]. An alternative strategy is to block NOTCH transcriptional complexes in the nucleus using chemically modified peptides. In this regard, the resolution of the NOTCH-RBPJ-MAML1 transcriptional complex [Nam et al. 2006] was instrumental in developing SAHM1, a stapled peptide designed to displace MAML1 and block the transcriptional activity of NOTCH1 RBPJ complex [Moellering et al. 2009].

Closing remarks

Clinical challenges remain ahead in the development of anti-NOTCH1 therapies in T-ALL. Logistically, relapsed T-ALL is a rare disease and patients at relapse typically show rapid disease progression making accruals in clinical trials slow. In addition, anti-NOTCH1 therapies may be most effective in the context of combination therapies, particularly with glucocorticoids, but possibly also with drugs targeting additionally important signaling pathways involved in the pathogenesis of T-ALL. Still, all GSI clinical trials designed to date have tested these drugs as single agents. However, it is worth noting the growing relevance of NOTCH1 as a therapeutic target outside T-ALL. The identification of prototypical activating mutations in NOTCH1 in chronic lymphocytic leukemia [Di Ianni et al. 2009; Fabbri et al. 2011; Puente et al. 2011] and the association of NOTCH1 mutations with advanced disease and chemotherapy resistance strongly suggest a potentially major role for anti NOTCH1 therapies in this disease. Similarly, rare but recurrent activating mutations in NOTCH1 have been found in lung cancer [Westhoff et al. 2009] and a pathogenic role for NOTCH signaling has been proposed other solid tumors [Roy et al. 2007; Shih Ie and Wang, 2007], with recent phase I clinical trials showing relevant results on the safety and potential therapeutic activity of GSIs in nonhematologic malignancies [Krop et al. 2012; Tolcher et al. 2012].

Footnotes

Funding

This work was supported by the National Institutes of Health (grant numbers R01CA120196 and R01CA129382 to A.A.F) and the Leukemia and Lymphoma Society (Scholar Award to A.A.F.)

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

References

Aplan

Lombardi

Ginsberg

Cossman

Bertness

Kirsch

(1990) Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity. Science 250: 1426–1429.

Asnafi

Buzyn

Le Noir

Baleydier

Simon

Beldjord

. (2009) NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood 113: 3918–3924.

Asnafi

Radford-Weiss

Dastugue

Bayle

Leboeuf

Charrin

. (2003) CALM-AF10 is a common fusion transcript in T-ALL and is specific to the TCRgammadelta lineage. Blood 102: 1000–1006.

Aste-Amezaga

Zhang

Lineberger

Arnold

Toner

. (2010) Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One 5(2): e9094.

Aster

Pear

Blacklow

(2008) Notch signaling in leukemia. Annu Rev Pathol 3: 587–613.

Balgobind

Van Vlierberghe

van den Ouweland

Beverloo

Terlouw-Kromosoeto

van Wering

. (2008) Leukemia-associated NF1 inactivation in patients with pediatric T-ALL and AML lacking evidence for neurofibromatosis. Blood 111: 4322–4328.

Bar-Eli

Ahuja

Foti

Cline

(1989) N-RAS mutations in T-cell acute lymphocytic leukaemia: analysis by direct sequencing detects a novel mutation. Br J Haematol 72: 36–39.

Begley

Aplan

Davey

Nakahara

Tchorz

Kurtzberg

. (1989) Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc Natl Acad Sci U S A 86: 2031–2035.

Ben Abdelali

Asnafi

Leguay

Boissel

Buzyn

Chevallier

. (2011) Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study. Blood 118: 5099–5107.

10.

Bernard

Guglielmi

Jonveaux

Cherif

Gisselbrecht

Mauchauffe

. (1990) Two distinct mechanisms for the SCL gene activation in the t(1;14) translocation of T-cell leukemias. Genes Chromosomes Cancer 1: 194–208.

11.

Boehm

Foroni

Kaneko

Perutz

Rabbitts

(1991) The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc Natl Acad Sci U S A 88: 4367–4371.

12.

Breit

Stanulla

Flohr

Schrappe

Ludwig

Tolle

. (2006) Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 108: 1151–1157.

13.

Brou

Logeat

Gupta

Bessia

LeBail

Doedens

. (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5: 207–216.

14.

Campbell

Der

(2004) Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol 14: 105–114.

15.

Carlson

Vignon

Bohlander

Martinez-Climent

Le Beau

Rowley

(2000) Identification and molecular characterization of CALM/AF10fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia. Leukemia 14: 100–104.

16.

Chan

Weng

Tibshirani

Aster

Utz

(2007) Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 110: 278–286.

17.

Chen

Cheng

Tasi

Schneider

Buchanan

Carroll

. (1990) The tal gene undergoes chromosome translocation in T cell leukemia and potentially encodes a helix-loop-helix protein. Embo J 9: 415–424.

18.

Chervinsky

Sait

Nowak

Shows

Aplan

(1995) Complex MLL rearrangement in a patient with T-cell acute lymphoblastic leukemia. Genes Chromosomes Cancer 14: 76–84.

19.

Ciofani

Zuniga-Pflucker

(2005) Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 6: 881–888.

20.

Clappier

Collette

Grardel

Girard

Suarez

Brunie

. (2010) 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 24: 2023–2031.

21.

Clappier

Cuccuini

Kalota

Crinquette

Cayuela

Dik

. (2007) The C-MYB locus is involved in chromosomal translocation and genomic duplications in human T-cell acute leukemia (T-ALL), the translocation defining a new T-ALL subtype in very young children. Blood 110: 1251–1261.

22.

Clurman

Sheaff

Thress

Groudine

Roberts

(1996) Turnover of cyclin E by the ubiquitin-proteasome pathway is regulated by cdk2 binding and cyclin phosphorylation. Genes Dev 10: 1979–1990.

23.

Cullion

Draheim

Hermance

Tammam

Sharma

Ware

. (2009) Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 113: 6172–6181.

24.

De Keersmaecker

Graux

Odero

Mentens

Somers

Maertens

. (2005) Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). Blood 105: 4849–4852.

25.

De Keersmaecker

Real

Gatta

Palomero

Sulis

Tosello

. (2010) The TLX1 oncogene drives aneuploidy in T cell transformation. Nat Med 16: 1321–1327.

26.

Deangelo

Stone

Silverman

Stock

Attar

Fearen

. (2006) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 24(18 Suppl.): 6585.

27.

Della Gatta

Palomero

Perez-Garcia

Ambesi-Impiombato

Bansal

Carpenter

. (2012) Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med 18: 436–440.

28.

Di Ianni

Baldoni

Rosati

Ciurnelli

Cavalli

Martelli

. (2009) A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol 146: 689–691.

29.

Dohda

Maljukova

Liu

Heyman

Grander

Brodin

. (2007) Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines. Exp Cell Res 313: 3141–3152.

30.

Dreyling

Martinez-Climent

Zheng

Mao

Rowley

Bohlander

(1996) The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family. Proc Natl Acad Sci U S A 93: 4804–4809.

31.

Dube

Kamel-Reid

Yuan

Corpus

. (1991) A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10;14). Blood 78: 2996–3003.

32.

Ellisen

Bird

West

Soreng

Reynolds

Smith

. (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66: 649–661.

33.

Erikson

Finger

Sun

ar-Rushdi

Nishikura

Minowada

. (1986) Deregulation of c-myc by translocation of the alpha-locus of the T-cell receptor in T-cell leukemias. Science 232: 884–886.

34.

Espinosa

Cathelin

D’Altri

Trimarchi

Statnikov

Guiu

. (2010) The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 18: 268–281.

35.

Fabbri

Rasi

Rossi

Trifonov

Khiabanian

. (2011) Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 208: 1389–1401.

36.

Ferrando

Look

(2000) Clinical implications of recurring chromosomal and associated molecular abnormalities in acute lymphoblastic leukemia. Semin Hematol 37: 381–395.

37.

Ferrando

Neuberg

Staunton

Loh

Huard

Raimondi

. (2002) Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1: 75–87.

38.

Finger

Kagan

Christopher

Kurtzberg

Hershfield

Nowell

. (1989) Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc Natl Acad Sci U S A 86: 5039–5043.

39.

Flex

Petrangeli

Stella

Chiaretti

Hornakova

Knoops

. (2008) Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia. J Exp Med 205: 751–758.

40.

Fryer

Lamar

Turbachova

Kintner

Jones

(2002) Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev 16: 1397–1411.

41.

Gonzalez-Garcia

Garcia-Peydro

Martin-Gayo

Ballestar

Esteller

Bornstein

. (2009) CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemia. J Exp Med 206: 779–791.

42.

Graux

Cools

Melotte

Quentmeier

Ferrando

Levine

. (2004) Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet 36: 1084–1089.

43.

Greenberg

Boehm

Sofroniew

Keynes

Barton

Norris

. (1990) Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system. Nature 344: 158–160.

44.

Grossmann

Kern

Harbich

Alpermann

Jeromin

Schnittger

. (2011) Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia. Haematologica 96: 1874–1877.

45.

Gutierrez

Sanda

Zhang

Grebliunaite

Dahlberg

. (2010) Inactivation of LEF1 in T-cell acute lymphoblastic leukemia. Blood 115: 2845–2851.

46.

Han

Tanigaki

Yamamoto

Kuroda

Yoshimoto

Nakahata

. (2002) Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int Immunol 14: 637–645.

47.

Hansen-Hagge

Schafer

Kiyoi

Morris

Whitlock

Koch

. (2002) Disruption of the RanBP17/Hox11L2 region by recombination with the TCRdelta locus in acute lymphoblastic leukemias with t(5;14)(q34;q11). Leukemia 16: 2205–2212.

48.

Hatano

Roberts

Minden

Crist

Korsmeyer

(1991) Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia. Science 253: 79–82.

49.

Haydu

De Keersmaecker

Duff

Paietta

Racevskis

Wiernik

. (2012) An activating intragenic deletion in NOTCH1 in human T-ALL. Blood 119: 5211–5214.

50.

Hebert

Cayuela

Berkeley

Sigaux

(1994) Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias. Blood 84: 4038–4044.

51.

Hozumi

Mailhos

Negishi

Hirano

Yahata

Ando

. (2008) Delta-like 4 is indispensable in thymic environment specific for T cell development. J Exp Med 205: 2507–2513.

52.

Hubbard

Kitajewski

Greenwald

(1997) sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins. Genes Dev 11: 3182–3193.

53.

Hussey

Nicola

Moore

Peters

Dobrovic

(1999) The (4;11)(q21;p15) translocation fuses the NUP98 and RAP1GDS1 genes and is recurrent in T-cell acute lymphocytic leukemia. Blood 94: 2072–2079.

54.

Inaba

Murakami

Oku

Itoh

Ura

Nakanishi

. (1990) Translocation between chromosomes 8q24 and 14q11 in T-cell acute lymphoblastic leukemia. Cancer Genet Cytogenet 49: 69–74.

55.

Inuzuka

Shaik

Onoyama

Gao

Tseng

Maser

. (2011) SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 471: 104–109.

56.

Joshi

Minter

Telfer

Demarest

Capobianco

Aster

. (2009) Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 113: 1689–1698.

57.

Karrman

Kjeldsen

Lassen

Isaksson

Davidsson

Andersson

. (2009) The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus. Br J Haematol 144: 546–551.

58.

Kennedy

Gonzalez-Sarmiento

Kees

Lampert

Dear

Boehm

. (1991) HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24. Proc Natl Acad Sci U S A 88: 8900–8904.

59.

Kleppe

Soulier

Asnafi

Mentens

Hornakova

Knoops

. (2011) PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia. Blood 117: 7090–7098.

60.

Krop

Demuth

Guthrie

Wen

Mason

Chinnaiyan

. (2012) Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 30: 2307–2313.

61.

Lahortiga

De Keersmaecker

Van Vlierberghe

Graux

Cauwelier

Lambert

. (2007) Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia. Nat Genet 39: 593–595.

62.

Gordon

Chang

. (2008) Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem 283: 8046–8054.

63.

Sanda

Look

Novina

von Boehmer

(2011) Repression of tumor suppressor miR-451 is essential for NOTCH1-induced oncogenesis in T-ALL. J Exp Med 208: 663–675.

64.

Lubman

O.Y.

Ilagan

M.X.

Kopan

Barrick

(2007) Quantitative dissection of the Notch:CSL interaction: insights into the Notch-mediated transcriptional switch. J Mol Biol 365: 577–589.

65.

Malyukova

Dohda

von der Lehr

Akhoondi

Corcoran

Heyman

. (2007) The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer Res 67: 5611–5616.

66.

Mansour

Sulis

Duke

Foroni

Jenkinson

Koo

. (2009) 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 27: 4352–4356.

67.

Mavrakis

Wolfe

Oricchio

Palomero

de Keersmaecker

McJunkin

. (2010) Genome-wide RNA-mediated interference screen identifies miR-19 targets in Notch-induced T-cell acute lymphoblastic leukaemia. Nat Cell Biol 12: 372–379.

68.

McGuire

Hockett

Pollock

Bartholdi

O’Brien

Korsmeyer

(1989) The t(11;14)(p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein. Mol Cell Biol 9: 2124–2132.

69.

Mecucci

La Starza

Negrini

Sabbioni

Crescenzi

Leoni

. (2000) t(4;11)(q21;p15) translocation involving NUP98 and RAP1GDS1 genes: characterization of a new subset of T acute lymphoblastic leukaemia. Br J Haematol 109: 788–793.

70.

Medyouf

Gao

Armstrong

Gusscott

Liu

Gedman

. (2010) Acute T-cell leukemias remain dependent on Notch signaling despite PTEN and INK4A/ARF loss. Blood 115: 1175–1184.

71.

Medyouf

Gusscott

Wang

Tseng

J.C.

Wai

Nemirovsky

. (2011) High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. J Exp Med 208: 1809–1822.

72.

Mellentin

Smith

Cleary

(1989) lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif. Cell 58: 77–83.

73.

Moellering

Cornejo

Davis

Del Bianco

Aster

Blacklow

. (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462: 182–188.

74.

Mumm

Kopan

(2000) Notch signaling: from the outside in. Dev Biol 228: 151–165.

75.

Nagel

Kaufmann

Drexler

MacLeod

R.A.

(2003) The cardiac homeobox gene NKX2-5 is deregulated by juxtaposition with BCL11B in pediatric T-ALL cell lines via a novel t(5;14)(q35.1;q32.2). Cancer Res 63: 5329–5334.

76.

Nagel

Scherr

Kel

Hornischer

Crawford

Kaufmann

. (2007) Activation of TLX3 and NKX2-5 in t(5;14)(q35;q32) T-cell acute lymphoblastic leukemia by remote 3’-BCL11B enhancers and coregulation by PU.1 and HMGA1. Cancer Res 67: 1461–1471.

77.

Nam

Sliz

Song

Aster

Blacklow

(2006) Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124: 973–983.

78.

Ntziachristos

Tsirigos

Van Vlierberghe

Nedjic

Trimarchi

Sol Flaherty

. (2012) Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia. Nat Med 18: 298–301.

79.

O’Neil

Grim

Strack

Rao

Tibbitts

Winter

. (2007a) FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 204: 1813–1824.

80.

O’Neil

Tchinda

Gutierrez

Moreau

Maser

Wong

. (2007b) Alu elements mediate MYB gene tandem duplication in human T-ALL. J Exp Med 204: 3059–3066.

81.

Oudot

Auclerc

Levy

Porcher

Piguet

Perel

. (2008) Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study. J Clin Oncol 26: 1496–1503.

82.

Paietta

Ferrando

Neuberg

Bennett

Racevskis

Lazarus

. (2004) Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood 104: 558–560.

83.

Palomero

Barnes

Real

Bender

Sulis

Murty

. (2006a) CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 20: 1279–1287.

84.

Palomero

Barnes

Real

Glade Bender

Sulis

Murty

. (2006b) CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 20: 1279–1287.

85.

Palomero

Lim

Odom

Sulis

Real

Margolin

. (2006c) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 103: 18261–18266.

86.

Palomero

Sulis

Cortina

Real

Barnes

Ciofani

. (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13: 1203–1210.

87.

Park

Taki

Oda

Watanabe

Yumura-Yagi

Kobayashi

. (2009) FBXW7 and NOTCH1 mutations in childhood T cell acute lymphoblastic leukaemia and T cell non-Hodgkin lymphoma. Br J Haematol 145: 198–206.

88.

Przybylski

Dik

Grabarczyk

Wanzeck

Chudobska

Jankowski

. (2006) The effect of a novel recombination between the homeobox gene NKX2-5 and the TRD locus in T-cell acute lymphoblastic leukemia on activation of the NKX2-5 gene. Haematologica 91: 317–321.

89.

Puente

X.S.

Pinyol

Quesada

Conde

Ordonez

G.R.

Villamor

. (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475: 101–105.

90.

Pui

Robison

Look

(2008) Acute lymphoblastic leukaemia. Lancet 371: 1030–1043.

91.

Radtke

Wilson

Stark

Bauer

van Meerwijk

MacDonald

. (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10: 547–558.

92.

Rao

O’Neil

Liberator

Hardwick

Dai

Zhang

. (2009) Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells. Cancer Res 69: 3060–3068.

93.

Real

Ferrando

(2009) NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23: 1374–1377.

94.

Real

Tosello

Palomero

Castillo

Hernando

de Stanchina

. (2009) Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 15: 50–58.

95.

Reizis

Leder

(2002) Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev 16: 295–300.

96.

Renneville

Kaltenbach

Clappier

Collette

Micol

Nelken

. (2010) Wilms tumor 1 (WT1) gene mutations in pediatric T-cell malignancies. Leukemia 24: 476–480.

97.

Riccio

van Gijn

Bezdek

Pellegrinet

van Es

Zimber-Strobl

. (2008) Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27(Kip1) and p57(Kip2). EMBO Rep 9: 377–383.

98.

Roy

Pear

Aster

(2007) The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17: 52–59.

99.

Royer-Pokora

Loos

Ludwig

W.D.

(1991) TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). Oncogene 6: 1887–1893.

100.

Rubnitz

Behm

Curcio-Brint

Pinheiro

Carroll

Raimondi

. (1996) Molecular analysis of t(11;19) breakpoints in childhood acute leukemias. Blood 87: 4804–4808.

101.

Samon

Castillo-Martin

Hadler

Ambesi-Impiombato

Paietta

Racevskis

. (2012) Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer Ther 11: 1565–1575.

102.

Sanda

Gutierrez

Ahn

Neuberg

O’Neil

. (2010) Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia. Blood 115: 1735–1745.

103.

Schmitt

Ciofani

Petrie

Zuniga-Pflucker

(2004) Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions. J Exp Med 200: 469–479.

104.

Sharma

Calvo

Draheim

Cunningham

Hermance

Beverly

. (2006) Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 26: 8022–8031.

105.

Shih Ie

Wang

(2007) Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67: 1879–1882.

106.

Shima-Rich

Harden

McKeithan

Rowley

Diaz

(1997) Molecular analysis of the t(8;14)(q24;q11) chromosomal breakpoint junctions in the T-cell leukemia line MOLT-16. Genes Chromosomes Cancer 20: 363–371.

107.

Shima

Le Beau

McKeithan

Minowada

Showe

Mak

. (1986) Gene encoding the alpha chain of the T-cell receptor is moved immediately downstream of c-myc in a chromosomal 8;14 translocation in a cell line from a human T-cell leukemia. Proc Natl Acad Sci U S A 83: 3439–3443.

108.

Soulier

Clappier

Cayuela

Regnault

Garcia-Peydro

Dombret

. (2005) HOXA genes are included in genetic and biologic networks defining human acute T-cell leukemia (T-ALL). Blood 106: 274–286.

109.

Della-Valle

Andre-Schmutz

Lemercier

Radford-Weiss

Ballerini

. (2006) HOX11L2/TLX3 is transcriptionally activated through T-cell regulatory elements downstream of BCL11B as a result of the t(5;14)(q35;q32). Blood 108: 4198–4201.

110.

Sugimoto

Himeno

(1992) Casein kinase II site of human centromere protein B (CENP-B) is phosphorylated in vitro. Biosci Biotechnol Biochem 56: 1174–1175.

111.

Sulis

Saftig

Ferrando

(2011) Redundancy and specificity of the metalloprotease system mediating oncogenic NOTCH1 activation in T-ALL. Leukemia 25: 1564–1569

112.

Sulis

Williams

Palomero

Tosello

Pallikuppam

Real

. (2008) NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 112: 733–740.

113.

Sundaram

Greenwald

(1993) Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. Genetics 135: 765–783.

114.

Tammam

Ware

Efferson

O’Neil

Rao

. (2009) Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol 158: 1183–1195.

115.

Tan

Sangfelt

Spruck

(2008) The Fbxw7/hCdc4 tumor suppressor in human cancer. Cancer Lett 271: 1–12.

116.

Tanigaki

Honjo

(2007) Regulation of lymphocyte development by Notch signaling. Nat Immunol 8: 451–456.

117.

Tatarek

Cullion

Ashworth

Gerstein

Aster

Kelliher

M.A.

(2011) Notch1 inhibition targets the leukemia-initiating cells in a Tal1/Lmo2 mouse model of T-ALL. Blood 118: 1579–1590.

118.

Thompson

Buonamici

Sulis

Palomero

Vilimas

Basso

. (2007) The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 204: 1825–1835.

119.

Tolcher

Messersmith

Mikulski

Papadopoulos

Kwak

Gibbon

. (2012) Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 30(19): 2348–2353.

120.

Tosello

Mansour

M.R.

Barnes

Paganin

Sulis

Jenkinson

. (2009) WT1 mutations in T-ALL. Blood 114: 1038–1045.

121.

Urashima

Iyori

Fujisawa

Hoshi

Akatsuka

Maekawa

(1992) Establishment and characteristics of a T-cell acute lymphoblastic leukemia cell line, JK-T1, with a chromosomal translocation between 8q24 and 14q13. Cancer Genet Cytogenet 64: 86–90.

122.

van Es

van Gijn

Riccio

van den Born

Vooijs

Begthel

. (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435: 959–963.

123.

Van Vlierberghe

Ambesi-Impiombato

Perez-Garcia

Haydu

Rigo

Hadler

. (2011) ETV6 mutations in early immature human T cell leukemias. J Exp Med 208: 2571–2579.

124.

Van Vlierberghe

Palomero

Khiabanian

Van der Meulen

Castillo

Van Roy

. (2010) PHF6 mutations in T-cell acute lymphoblastic leukemia. Nat Genet 42: 338–342.

125.

Van Vlierberghe

van Grotel

Beverloo

Lee

Helgason

Buijs-Gladdines

. (2006) The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood 108: 3520–3529.

126.

Van Vlierberghe

van Grotel

Beverloo

Lee

Beverloo

van der Spek

. (2008) The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia. Blood 111: 4668–4680.

127.

Vilimas

Mascarenhas

Palomero

Mandal

Buonamici

Meng

. (2007) Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia. Nat Med 13: 70–77.

128.

Wang

Jani-Sait

Escalon

Carroll

de Jong

Kirsch

. (2000) The t(14;21)(q11.2;q22) chromosomal translocation associated with T-cell acute lymphoblastic leukemia activates the BHLHB1 gene. Proc Natl Acad Sci U S A 97: 3497–3502.

129.

Warren

Colledge

Carlton

Evans

Smith

Rabbitts

(1994) The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development. Cell 78: 45–57.

130.

Wei

Walls

Qiu

Ding

Denlinger

Wong

. (2010) Evaluation of selective gamma-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther 9: 1618–1628.

131.

Wei

Jin

Schlisio

Harper

Kaelin

Jr (2005) The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. Cancer Cell 8: 25–33.

132.

Weng

Ferrando

Lee

Morris

Silverman

Sanchez-Irizarry

. (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269–271.

133.

Weng

Millholland

Yashiro-Ohtani

Arcangeli

Lau

Wai

. (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20: 2096–2109.

134.

Westhoff

Colaluca

D’Ario

Donzelli

Tosoni

Volorio

. (2009) Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci U S A 106: 22293–22298.

135.

Wolfer

Wilson

Nemir

MacDonald

Radtke

(2002) Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta lineage thymocytes. Immunity 16: 869–879.

136.

Cain-Hom

Choy

Hagenbeek

de Leon

Chen

. (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464: 1052–1057.

137.

Xia

Brown

Yang

Tsan

Siciliano

Espinosa

III . (1991) TAL2, a helix-loop-helix gene activated by the (7;9)(q34;q32) translocation in human T-cell leukemia. Proc Natl Acad Sci U S A 88: 11416–11420.

138.

Zenatti

Ribeiro

Zuurbier

Silva

Paganin

. (2011) Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet 43: 932–939.

139.

Zhang

Ding

Holmfeldt

Heatley

Payne-Turner

. (2012) The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481: 157–163.

140.

Zuurbier

Homminga

Calvert

te Winkel

Buijs-Gladdines

Kooi

. (2010) NOTCH1 and/or FBXW7 mutations predict for initial good prednisone response but not for improved outcome in pediatric T-cell acute lymphoblastic leukemia patients treated on DCOG or COALL protocols. Leukemia 24: 2014–2022.

The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy

Abstract

Keywords

Clinical challenges and molecular features of T-ALL

The NOTCH1 signaling pathway

NOTCH1 signaling in normal T-cell development

NOTCH1 signaling in T-ALL

Genes and pathways deregulated by activated NOTCH1 in T-ALL

Clinical impact of aberrant NOTCH1 signaling in T-ALL

Gamma secretase inhibitors, an emerging targeted therapy for T-ALL

Novel approaches for NOTCH1 inhibition

Closing remarks

Footnotes

Funding

Conflict of interest statement

References