{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T23:01:34Z","timestamp":1765666894379,"version":"build-2065373602"},"reference-count":129,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2010,11,5]],"date-time":"2010-11-05T00:00:00Z","timestamp":1288915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Two main NF-\u03baB signaling pathways, canonical and noncanonical, performing distinct functions in organisms have been characterized. Identification of mutations in genes encoding components of these NF-\u03baB signaling pathways in lymphoid malignancies confirmed their key role in leukemogenesis. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes that despite significant therapeutic advances can still be fatal. Although mutations in NF-\u03baB genes have not been reported in T-ALL, NF-\u03baB constitutive activation in human T-ALL and in acute T-cell leukemia mouse models has been observed. Although these studies revealed activation of members of both canonical and noncanonical NF-\u03baB pathways in acute T-cell leukemia, only inhibition of canonical NF-\u03baB signaling was shown to impair leukemic T cell growth. Besides playing an important pro-oncogenic role in leukemic T cells, NF-\u03baB signaling also appears to modulate T-cell leukemogenesis through its action in microenvironmental stromal cells. This article reviews recent data on the role of these transcription factors in T-ALL and pinpoints further research crucial to determine the value of NF-\u03baB inhibition as a means to treat T-ALL.<\/jats:p>","DOI":"10.3390\/cancers2041838","type":"journal-article","created":{"date-parts":[[2010,11,5]],"date-time":"2010-11-05T12:08:19Z","timestamp":1288958899000},"page":"1838-1860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["NF-\u03baB in T-cell Acute Lymphoblastic Leukemia: Oncogenic Functions in Leukemic and in Microenvironmental Cells"],"prefix":"10.3390","volume":"2","author":[{"given":"Nuno R.","family":"Dos Santos","sequence":"first","affiliation":[{"name":"IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}]},{"given":"Marinella N.","family":"Ghezzo","sequence":"additional","affiliation":[{"name":"IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}]},{"given":"Ricardo C.","family":"Da Silva","sequence":"additional","affiliation":[{"name":"IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}]},{"given":"M\u00f3nica T.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"IBB-Institute for Biotechnology and Bioengineering, Centre for Molecular and Structural Biomedicine (CBME), University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2010,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6831","DOI":"10.1038\/sj.onc.1209939","article-title":"Mutations in the NF-\u03baB signaling pathway: Implications for human disease","volume":"25","author":"Courtois","year":"2006","journal-title":"Oncogene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6817","DOI":"10.1038\/sj.onc.1209942","article-title":"Nuclear factor-\u03baB and inhibitor of \u03baB kinase pathways in oncogenic initiation and progression","volume":"25","author":"Baldwin","year":"2006","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nature04870","article-title":"Nuclear factor-\u03baB in cancer development and progression","volume":"441","author":"Karin","year":"2006","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-\u03baB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1146\/annurev.immunol.021908.132641","article-title":"Regulation and function of NF-\u03baB transcription factors in the immune system","volume":"27","author":"Vallabhapurapu","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1126\/science.284.5412.316","article-title":"Abnormal morphogenesis but intact IKK activation in mice lacking the IKK\u03b1 subunit of I\u03baB kinase","volume":"284","author":"Hu","year":"1999","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1126\/science.284.5412.321","article-title":"Severe liver degeneration in mice lacking the I\u03baB kinase 2 gene","volume":"284","author":"Li","year":"1999","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1101\/gad.13.10.1322","article-title":"IKK1-deficient mice exhibit abnormal development of skin and skeleton","volume":"13","author":"Li","year":"1999","journal-title":"Genes Dev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1084\/jem.189.11.1839","article-title":"The IKK\u03b2 subunit of I\u03baB kinase (IKK) is essential for nuclear factor \u03baB activation and prevention of apoptosis","volume":"189","author":"Li","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1101\/gad.14.7.854","article-title":"Severe liver degeneration and lack of NF-\u03baB activation in NEMO\/IKK\u03b3-deficient mice","volume":"14","author":"Rudolph","year":"2000","journal-title":"Genes Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1126\/science.284.5412.313","article-title":"Limb and skin abnormalities in mice lacking IKK\u03b1","volume":"284","author":"Takeda","year":"1999","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26243","DOI":"10.1074\/jbc.M403286200","article-title":"Regulation of the NF-\u03baB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation","volume":"279","author":"Liao","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/ni.1676","article-title":"Noncanonical NF-\u03baB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK","volume":"9","author":"Zarnegar","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1038\/ni.1678","article-title":"Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-\u03baB signaling","volume":"9","author":"Vallabhapurapu","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"30099","DOI":"10.1074\/jbc.M401428200","article-title":"Induction of p100 processing by NF-\u03baB-inducing kinase involves docking I\u03baB kinase \u03b1 (IKK\u03b1) to p100 and IKK\u03b1-mediated phosphorylation","volume":"279","author":"Xiao","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23278","DOI":"10.1074\/jbc.M300106200","article-title":"RelB\/p50 dimers are differentially regulated by tumor necrosis factor-\u03b1 and lymphotoxin-\u03b2 receptor activation: Critical roles for p100","volume":"278","author":"Derudder","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cell.2006.12.033","article-title":"A fourth I\u03baB protein within the NF-\u03baB signaling module","volume":"128","author":"Basak","year":"2007","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S1074-7613(02)00423-5","article-title":"The lymphotoxin-\u03b2 receptor induces different patterns of gene expression via two NF-\u03baB pathways","volume":"17","author":"Dejardin","year":"2002","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"12006","DOI":"10.1074\/jbc.M210768200","article-title":"Lymphotoxin \u03b2 receptor induces sequential activation of distinct NF-\u03baB factors via separate signaling pathways","volume":"278","author":"Siebenlist","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/emboj\/cdg004","article-title":"RelB is required for Peyer's patch development: Differential regulation of p52-RelB by lymphotoxin and TNF","volume":"22","author":"Yilmaz","year":"2003","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7722","DOI":"10.1038\/sj.onc.1204868","article-title":"Transcription of the RelB gene is regulated by NF-\u03baB","volume":"20","author":"Bren","year":"2001","journal-title":"Oncogene"},{"key":"ref_22","first-page":"7695","article-title":"Transcriptional regulation of NF-\u03baB2: Evidence for \u03baB-mediated positive and negative autoregulation","volume":"14","author":"Liptay","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1128\/MCB.01469-07","article-title":"Generation and activation of multiple dimeric transcription factors within the NF-\u03baB signaling system","volume":"28","author":"Basak","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"ra41","DOI":"10.1126\/scisignal.2000778","article-title":"Negative feedback in noncanonical NF-\u03baB signaling modulates NIK stability through IKK\u03b1-mediated phosphorylation","volume":"3","author":"Razani","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/j.immuni.2004.08.009","article-title":"Receptor-specific signaling for both the alternative and the canonical NF-\u03baB activation pathways by NF-\u03baB-inducing kinase","volume":"21","author":"Ramakrishnan","year":"2004","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1073\/pnas.0707959105","article-title":"Control of canonical NF-\u03baB activation through the NIK-IKK complex pathway","volume":"105","author":"Zarnegar","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1182\/blood-2006-07-025809","article-title":"Aberrant NF-\u03baB signaling in lymphoma: Mechanisms, consequences, and therapeutic implications","volume":"109","author":"Jost","year":"2007","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1365-2141.2008.07284.x","article-title":"The role of NF-\u03baB in lymphoid malignancies","volume":"143","author":"Packham","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.ccr.2007.07.004","article-title":"Frequent engagement of the classical and alternative NF-\u03baB pathways by diverse genetic abnormalities in multiple myeloma","volume":"12","author":"Annunziata","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ccr.2007.07.003","article-title":"Promiscuous mutations activate the noncanonical NF-\u03baB pathway in multiple myeloma","volume":"12","author":"Keats","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5887","DOI":"10.1158\/1078-0432.CCR-05-2501","article-title":"MLN120B, a novel I\u03baB kinase \u03b2 inhibitor, blocks multiple myeloma cell growth in vitro and in vivo","volume":"12","author":"Hideshima","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nature07968","article-title":"Mutations of multiple genes cause deregulation of NF-\u03baB in diffuse large B-cell lymphoma","volume":"459","author":"Compagno","year":"2009","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/nature07969","article-title":"Frequent inactivation of A20 in B-cell lymphomas","volume":"459","author":"Kato","year":"2009","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1126\/science.1153629","article-title":"Oncogenic CARD11 mutations in human diffuse large B cell lymphoma","volume":"319","author":"Lenz","year":"2008","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1038\/sj.onc.1205337","article-title":"Ligand-independent signaling by overexpressed CD30 drives NF-\u03baB activation in Hodgkin-Reed-Sternberg cells","volume":"21","author":"Horie","year":"2002","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1182\/blood.V96.8.2841","article-title":"Hodgkin disease: Pharmacologic intervention of the CD40-NF-\u03baB pathway by a protease inhibitor","volume":"96","author":"Annunziata","year":"2000","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1182\/blood-2006-06-027755","article-title":"BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-\u03baB pathway","volume":"109","author":"Endo","year":"2007","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1182\/blood-2003-06-1984","article-title":"BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone","volume":"103","author":"Moreaux","year":"2004","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1182\/blood-2004-02-0762","article-title":"Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: Correlation with disease activity and patient outcome","volume":"104","author":"Novak","year":"2004","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/sj.leu.2403998","article-title":"The NF-\u03baB pathway blockade by the IKK inhibitor PS1145 can overcome imatinib resistance","volume":"20","author":"Cilloni","year":"2006","journal-title":"Leukemia"},{"key":"ref_41","first-page":"853","article-title":"The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr\/Abl-positive cell lines sensitive and resistant to imatinib mesylate","volume":"88","author":"Gatto","year":"2003","journal-title":"Haematologica"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1158\/1535-7163.MCT-07-0305","article-title":"I\u03baB kinase \u03b2 inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells","volume":"7","author":"Duncan","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"8081","DOI":"10.1073\/pnas.95.14.8081","article-title":"Evidence for a role of NF-\u03baB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL\/platelet-derived growth factor receptor \u03b2 fusion protein","volume":"95","author":"Atfi","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1309\/2QE3A6EKQ8UYDYRC","article-title":"Precursor T-cell acute lymphoblastic leukemia\/lymphoblastic lymphoma and acute biphenotypic leukemias","volume":"127","author":"Han","year":"2007","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cancergencyto.2009.01.002","article-title":"High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage","volume":"191","author":"Schraders","year":"2009","journal-title":"Cancer Genet. Cytogenet"},{"key":"ref_46","first-page":"1116","article-title":"Genetic insights in the pathogenesis of T-cell acute lymphoblastic leukemia","volume":"90","author":"Marynen","year":"2005","journal-title":"Haematologica"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nri2304","article-title":"Molecular pathogenesis of T-cell leukaemia and lymphoma","volume":"8","author":"Aifantis","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/sj.leu.2404302","article-title":"Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: From thymocyte to lymphoblast","volume":"20","author":"Graux","year":"2006","journal-title":"Leukemia"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/j.1365-2141.2008.07314.x","article-title":"Molecular-genetic insights in paediatric T-cell acute lymphoblastic leukaemia","volume":"143","author":"Pieters","year":"2008","journal-title":"Br. J. Haematol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.1102160","article-title":"Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia","volume":"306","author":"Weng","year":"2004","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.1182\/blood.V87.6.2180.bloodjournal8762180","article-title":"Multiple tumor-suppressor gene 1 inactivation is the most frequent genetic alteration in T-cell acute lymphoblastic leukemia","volume":"87","author":"Cayuela","year":"1996","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1084\/jem.20072182","article-title":"Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia","volume":"205","author":"Flex","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0925-5710(98)00015-2","article-title":"Mutational analysis of the N-ras gene in acute lymphoblastic leukemia: A study of 125 Japanese pediatric cases","volume":"67","author":"Yokota","year":"1998","journal-title":"Int. J. Hematol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1182\/blood-2004-01-0168","article-title":"Activating FLT3 mutations in CD117\/KIT+ T-cell acute lymphoblastic leukemias","volume":"104","author":"Paietta","year":"2004","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/ng1425","article-title":"Fusion of NUP214 to ABL1 on amplified episomes in T-cell acute lymphoblastic leukemia","volume":"36","author":"Graux","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1182\/blood-2006-12-064683","article-title":"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","volume":"110","author":"Clappier","year":"2007","journal-title":"Blood"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/ng2025","article-title":"Duplication of the MYB oncogene in T cell acute lymphoblastic leukemia","volume":"39","author":"Lahortiga","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1084\/jem.20070876","article-title":"FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to \u03b3-secretase inhibitors","volume":"204","author":"Grim","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1172\/JCI34616","article-title":"PTEN posttranslational inactivation and hyperactivation of the PI3K\/Akt pathway sustain primary T cell leukemia viability","volume":"118","author":"Silva","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/nm1636","article-title":"Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia","volume":"13","author":"Palomero","year":"2007","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1182\/blood-2009-07-234377","article-title":"LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B cell lymphocytosis","volume":"115","author":"Gutierrez","year":"2010","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/ng.587","article-title":"Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia","volume":"42","author":"Kleppe","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/ng.542","article-title":"PHF6 mutations in T-cell acute lymphoblastic leukemia","volume":"42","author":"Palomero","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1590\/S0100-879X2008005000016","article-title":"Aberrant signaling in T-cell acute lymphoblastic leukemia: Biological and therapeutic implications","volume":"41","author":"Cardoso","year":"2008","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3324\/haematol.12917","article-title":"Signaling pathways involved in the development of T-cell acute lymphoblastic leukemia","volume":"93","author":"Staal","year":"2008","journal-title":"Haematologica"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/sj.leu.2401705","article-title":"Transcription factor NF-\u03baB is constitutively activated in acute lymphoblastic leukemia cells","volume":"14","author":"Kordes","year":"2000","journal-title":"Leukemia"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/nm1524","article-title":"Targeting the NF-\u03baB signaling pathway in Notch1-induced T-cell leukemia","volume":"13","author":"Vilimas","year":"2007","journal-title":"Nat. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1093\/emboj\/19.13.3337","article-title":"Constitutive activation of NF-\u03baB and T-cell leukemia\/lymphoma in Notch3 transgenic mice","volume":"19","author":"Bellavia","year":"2000","journal-title":"EMBO J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e2555","DOI":"10.1371\/journal.pone.0002555","article-title":"RelB-dependent stromal cells promote T-cell leukemogenesis","volume":"3","author":"Williame","year":"2008","journal-title":"PLoS ONE"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.1182\/blood-2003-01-0090","article-title":"NF-\u03baB activation in premalignant mouse tal-1\/scl thymocytes and tumors","volume":"102","author":"Ventura","year":"2003","journal-title":"Blood"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ccr.2010.08.006","article-title":"The Notch\/Hes1 pathway sustains NF-\u03baB activation through CYLD repression in T cell leukemia","volume":"18","author":"Espinosa","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/j.leukres.2005.05.004","article-title":"Inhibition of NF-\u03baB activity by BAY 11-7082 increases apoptosis in multidrug resistant leukemic T-cell lines","volume":"29","author":"Alaniz","year":"2005","journal-title":"Leuk. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/cr.2008.30","article-title":"The I\u03baB kinase - a bridge between inflammation and cancer","volume":"18","author":"Karin","year":"2008","journal-title":"Cell Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1096\/fj.06-7615rev","article-title":"Beyond I\u03baBs: Alternative regulation of NF-\u03baB activity","volume":"21","author":"Neumann","year":"2007","journal-title":"FASEB J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"416","DOI":"10.4049\/jimmunol.147.2.416","article-title":"Physiologic activation of T cells via the T cell receptor induces NF-\u03baB","volume":"147","author":"Jamieson","year":"1991","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/87704","article-title":"Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-\u03baB and NFAT","volume":"2","author":"Aifantis","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/S1074-7613(00)00067-4","article-title":"NF-\u03baB activation by the pre-T cell receptor serves as a selective survival signal in T lymphocyte development","volume":"13","author":"Voll","year":"2000","journal-title":"Immunity"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/nri1944","article-title":"The CARMA1 signalosome links the signalling machinery of adaptive and innate immunity in lymphocytes","volume":"6","author":"Rawlings","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.1038\/sj.onc.1203018","article-title":"A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue","volume":"18","author":"Akagi","year":"1999","journal-title":"Oncogene"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1182\/blood.V93.11.3601","article-title":"The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas","volume":"93","author":"Dierlamm","year":"1999","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/intimm\/9.1.127","article-title":"Role of thymic selection in the development of thymic lymphomas in TCR transgenic mice","volume":"9","author":"Strzadala","year":"1997","journal-title":"Int. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nature08638","article-title":"Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma","volume":"463","author":"Davis","year":"2010","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2693","DOI":"10.1182\/blood-2002-08-2438","article-title":"Analysis of TCR, pT\u03b1, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment","volume":"101","author":"Asnafi","year":"2003","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0145-2126(98)00133-7","article-title":"Heterogeneity of T-acute lymphoblastic leukemia (T-ALL) cell lines: Suggestion for classification by immunophenotype and T-cell receptor studies","volume":"23","author":"Burger","year":"1999","journal-title":"Leuk. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/sj.emboj.7600996","article-title":"Notch3 and pre-TCR interaction unveils distinct Dierlamm, J.; Baens, M pathways in T-cell development and leukemia","volume":"25","author":"Vacca","year":"2006","journal-title":"EMBO J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"18261","DOI":"10.1073\/pnas.0606108103","article-title":"NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth","volume":"103","author":"Palomero","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/labinvest.3700700","article-title":"Off the beaten pathway: The complex cross talk between Notch and NF-\u03baB","volume":"88","author":"Osipo","year":"2008","journal-title":"Lab. Invest."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1128\/MCB.18.4.2077","article-title":"NF-\u03baB2 is a putative target gene of activated Notch-1 via RBP-J\u03ba","volume":"18","author":"Oswald","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/sj.emboj.7600902","article-title":"Notch1 augments NF-\u03baB activity by facilitating its nuclear retention","volume":"25","author":"Shin","year":"2006","journal-title":"EMBO J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"5833","DOI":"10.1038\/onc.2008.190","article-title":"Notch-1 associates with IKK\u03b1 and regulates IKK activity in cervical cancer cells","volume":"27","author":"Song","year":"2008","journal-title":"Oncogene"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"6008","DOI":"10.1158\/0008-5472.CAN-06-0194","article-title":"NFKB1 is a direct target of the TAL1 oncoprotein in human T leukemia cells","volume":"66","author":"Chang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1182\/blood.V95.12.3891","article-title":"TEL-JAK2 transgenic mice develop T-cell leukemia","volume":"95","author":"Carron","year":"2000","journal-title":"Blood"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/sj.leu.2404026","article-title":"A transgenic mouse model for TEL-JAK2-induced B-cell lymphoma\/leukemia","volume":"20","author":"Ghysdael","year":"2006","journal-title":"Leukemia"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.278.5341.1309","article-title":"A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia","volume":"278","author":"Lacronique","year":"1997","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1182\/blood.V90.7.2535","article-title":"Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia","volume":"90","author":"Peeters","year":"1997","journal-title":"Blood"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1093\/emboj\/17.18.5321","article-title":"Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL\/JAK2 fusion genes","volume":"17","author":"Schwaller","year":"1998","journal-title":"EMBO J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.1038\/sj.onc.1209390","article-title":"Activation of the NF-\u03baB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKK\u03b1","volume":"25","author":"Malinge","year":"2006","journal-title":"Oncogene"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0014-5793(01)02452-8","article-title":"Involvement of the NF-\u03baB pathway in the transforming properties of the TEL-Jak2 leukemogenic fusion protein","volume":"497","author":"Santos","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1182\/blood.V84.4.1232.1232","article-title":"Molecular analysis of the T-cell acute lymphoblastic leukemia-associated t(1;7)(p34;q34) that fuses LCK and TCRB","volume":"84","author":"Burnett","year":"1994","journal-title":"Blood"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1046\/j.1432-1327.2001.02028.x","article-title":"Tyrosine phosphorylation-dependent activation of NF-\u03baB. Requirement for p56 LCK and ZAP-70 protein tyrosine kinases","volume":"268","author":"Livolsi","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1038\/sj.onc.1201411","article-title":"Activation of p65 NF-\u03baB protein by p210BCR-ABL in a myeloid cell line (P210BCR-ABL activates p65 NF-\u03baB)","volume":"15","author":"Hamdane","year":"1997","journal-title":"Oncogene"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1101\/gad.12.7.968","article-title":"A requirement for NF-\u03baB activation in Bcr-Abl-mediated transformation","volume":"12","author":"Reuther","year":"1998","journal-title":"Genes Dev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1128\/MCB.26.6.2327-2336.2006","article-title":"CARMA1 is required for Akt-mediated NF-\u03baB activation in T cells","volume":"26","author":"Narayan","year":"2006","journal-title":"Mol. Cell. Biol"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7607","DOI":"10.4049\/jimmunol.177.11.7607","article-title":"ERK5 activates NF-\u03baB in leukemic T cells and is essential for their growth in vivo","volume":"177","author":"Garaude","year":"2006","journal-title":"J.Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1146\/annurev.pathol.1.110304.100224","article-title":"Tumor stroma and regulation of cancer development","volume":"1","author":"Tlsty","year":"2006","journal-title":"Annu. Rev. Pathol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/sj.leu.2404970","article-title":"Lymphoma microenvironment: Culprit or innocent?","volume":"22","author":"Herreros","year":"2008","journal-title":"Leukemia"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3972","DOI":"10.1182\/blood-2006-09-048801","article-title":"Pre-TCR expression cooperates with TEL-JAK2 to transform immature thymocytes and induce T-cell leukemia","volume":"109","author":"Rickman","year":"2007","journal-title":"Blood"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1038\/373531a0","article-title":"Expression of relB is required for the development of thymic medulla and dendritic cells","volume":"373","author":"Burkly","year":"1995","journal-title":"Nature"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1182\/blood-2006-02-004531","article-title":"Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells","volume":"108","author":"Gray","year":"2006","journal-title":"Blood"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/0092-8674(95)90416-6","article-title":"Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-\u03baB\/Rel family","volume":"80","author":"Weih","year":"1995","journal-title":"Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S1074-7613(00)80649-4","article-title":"RelB is essential for the development of myeloid-related CD8\u03b1-  dendritic cells but not of lymphoid-related CD8\u03b1+ dendritic cells","volume":"9","author":"Wu","year":"1998","journal-title":"Immunity"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4202","DOI":"10.1038\/sj.emboj.7600391","article-title":"Activation of IKK\u03b1 target genes depends on recognition of specific \u03baB binding sites by RelB:p52 dimers","volume":"23","author":"Bonizzi","year":"2004","journal-title":"EMBO J."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/nature08020","article-title":"CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia","volume":"459","author":"Buonamici","year":"2009","journal-title":"Nature"},{"key":"ref_114","first-page":"1229","article-title":"Thymic epithelial cells promote survival of human T-cell acute lymphoblastic leukemia blasts: The role of interleukin-7","volume":"88","author":"Scupoli","year":"2003","journal-title":"Haematologica"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"264","DOI":"10.3324\/haematol.10356","article-title":"Interleukin 7 requirement for survival of T-cell acute lymphoblastic leukemia and human thymocytes on bone marrow stroma","volume":"92","author":"Scupoli","year":"2007","journal-title":"Haematologica"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1158\/0008-5472.CAN-08-2791","article-title":"Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy","volume":"69","author":"Indraccolo","year":"2009","journal-title":"Cancer Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3793","DOI":"10.1182\/blood.V98.13.3793","article-title":"A novel Notch ligand, Dll4, induces T-cell leukemia\/lymphoma when overexpressed in mice by retroviral-mediated gene transfer","volume":"98","author":"Yan","year":"2001","journal-title":"Blood"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/S0140-6736(08)60457-2","article-title":"Acute lymphoblastic leukaemia","volume":"371","author":"Pui","year":"2008","journal-title":"Lancet"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1182\/blood.V89.6.1845","article-title":"Apoptosis and the dilemma of cancer chemotherapy","volume":"89","author":"Hannun","year":"1997","journal-title":"Blood"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"14914","DOI":"10.1074\/jbc.272.23.14914","article-title":"Activation of NF-\u03baB by antineoplastic agents. Role of protein kinase C","volume":"272","author":"Das","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nrc1588","article-title":"Nuclear factor-\u03baB inhibitors as sensitizers to anticancer drugs","volume":"5","author":"Nakanishi","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1172\/JCI11991","article-title":"Control of oncogenesis and cancer therapy resistance by the transcription factor NF-\u03baB","volume":"107","author":"Baldwin","year":"2001","journal-title":"J. Clin. Invest."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1158\/1541-7786.MCR-05-0028","article-title":"Enhanced G2-M arrest by nuclear factor-\u03baB-dependent p21waf1\/cip1 induction","volume":"3","author":"Chang","year":"2005","journal-title":"Mol. Cancer Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1158\/0008-5472.CAN-08-4884","article-title":"Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia","volume":"69","author":"Chiarini","year":"2009","journal-title":"Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"6172","DOI":"10.1182\/blood-2008-02-136762","article-title":"Targeting the Notch1 and mTOR pathways in a mouse T-ALL model","volume":"113","author":"Cullion","year":"2009","journal-title":"Blood"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/nature08543","article-title":"Direct inhibition of the NOTCH transcription factor complex","volume":"462","author":"Moellering","year":"2009","journal-title":"Nature"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"7579","DOI":"10.1158\/0008-5472.CAN-04-0641","article-title":"CC chemokine ligand 25 enhances resistance to apoptosis in CD4+ T cells from patients with T-cell lineage acute and chronic lymphocytic leukemia by means of livin activation","volume":"64","author":"Qiuping","year":"2004","journal-title":"Cancer Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1046\/j.1365-2141.2001.03164.x","article-title":"High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia","volume":"115","author":"Crazzolara","year":"2001","journal-title":"Br. J. Haematol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1046\/j.1365-2141.2001.03182.x","article-title":"Enhanced T-lineage acute lymphoblastic leukaemia cell survival on bone marrow stroma requires involvement of LFA-1 and ICAM-1","volume":"115","author":"Winter","year":"2001","journal-title":"Br. J. Haematol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/2\/4\/1838\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:03:46Z","timestamp":1760220226000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/2\/4\/1838"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,11,5]]},"references-count":129,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2010,12]]}},"alternative-id":["cancers2041838"],"URL":"https:\/\/doi.org\/10.3390\/cancers2041838","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2010,11,5]]}}}