Photo of Jon C. Aster,  MD, PhD

Jon C. Aster, MD, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-4406


jaster@partners.org

Jon C. Aster, MD, PhD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Pathology, Harvard Medical School
  • Associate Pathologist, Pathology, Brigham And Women's Hospital

DF/HCC PROGRAM AFFILIATION

DF/HCC ASSOCIATIONS

  • Member, Center Scientific Council
  • Institutional Representative for BWH, Membership Committee
  • Co-Chair, Membership Committee
  • Deputy Associate Director, Membership, Executive Committee
  • Member, Clinical Science Coordinating Committee

Research Abstract

My lab is focused on understanding the pathogenesis of Notch1-induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Notch1 (N1) is a member of a family of structurally-unique single-pass transmembrane receptors that regulate cellular differentiation through a novel type of signal transduction pathway. Normal N1 activation is triggered by ligand-dependent proteolytic cleavages that result in the release of the intracellular portion of N1 (ICN1), which then translocates to the nucleus and forms a transcription activation complex with the DNA-binding factor RBP-Jk/CSL and co-activators of the mastermind family. In 2004, we discovered frequent "gain-of-function" point mutations involving NOTCH1 in T-ALLs lacking the t(7;9). These mutations, depending on their location, either increase the rate of proteolysis and generation of ICN1, or enhance the stability of ICN1. ICN1 turns on a number of downstream targets, including c-Myc and components of the mTOR pathway, that support the growth and proliferation of T-ALL cells. Current activities include studies aimed at understanding in detail how Notch1 mutations act to increase ICN1 production and stability; the nature of the cross-talk between Notch1, mTOR, and other pathways that regulate cellular metabolism; the development of novel inhibitors that are selective for Notch1; and the identification and application of small molecules that act synergistically with Notch pathway inhibitors against tumor cells that depend on Notch signals.

Publications

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  • Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH. Ibrutinib in previously treated Waldenstr旦m's macroglobulinemia. N Engl J Med 2015; 372:1430-40. PubMed
  • Lin MI, Price EN, Boatman S, Hagedorn EJ, Trompouki E, Satishchandran S, Carspecken CW, Uong A, DiBiase A, Yang S, Canver MC, Dahlberg A, Lu Z, Zhang CC, Orkin SH, Bernstein ID, Aster JC, White RM, Zon LI. Angiopoietin-like proteins stimulate HSPC development through interaction with notch receptor signaling. Elife 2015. PubMed
  • Knoechel B, Roderick JE, Williamson KE, Zhu J, Lohr JG, Cotton MJ, Gillespie SM, Fernandez D, Ku M, Wang H, Piccioni F, Silver SJ, Jain M, Pearson D, Kluk MJ, Ott CJ, Shultz LD, Brehm MA, Greiner DL, Gutierrez A, Stegmaier K, Kung AL, Root DE, Bradner JE, Aster JC, Kelliher MA, Bernstein BE. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat Genet 2014; 46:364-70. PubMed
  • South AP, Purdie KJ, Watt SA, Haldenby S, den Breems NY, Dimon M, Arron ST, Kluk MJ, Aster JC, McHugh A, Xue DJ, Dayal JH, Robinson KS, Rizvi SM, Proby CM, Harwood CA, Leigh IM. NOTCH1 Mutations Occur Early during Cutaneous Squamous Cell Carcinogenesis. J Invest Dermatol 2014. PubMed
  • Gerhardt DM, Pajcini KV, D'altri T, Tu L, Jain R, Xu L, Chen MJ, Rentschler S, Shestova O, Wertheim GB, Tobias JW, Kluk M, Wood AW, Aster JC, Gimotty PA, Epstein JA, Speck N, Bigas A, Pear WS. The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev 2014; 28:576-93. PubMed
  • Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, Du J, Kazi JU, Luciano F, Rönnstrand L, Kung AL, Aster JC, Galinsky I, Stone RM, DeAngelo DJ, Hemann MT, Stegmaier K. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 2014; 25:226-42. PubMed
  • Gutierrez A, Pan L, Groen RW, Baleydier F, Kentsis A, Marineau J, Grebliunaite R, Kozakewich E, Reed C, Pflumio F, Poglio S, Uzan B, Clemons P, VerPlank L, An F, Burbank J, Norton S, Tolliday N, Steen H, Weng AP, Yuan H, Bradner JE, Mitsiades C, Look AT, Aster JC. Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. J Clin Invest 2014; 124:644-55. PubMed
  • O'Neill AF, Dearling JL, Wang Y, Tupper T, Sun Y, Aster JC, Calicchio ML, Perez-Atayde AR, Packard AB, Kung AL. Targeted imaging of Ewing sarcoma in preclinical models using a 64Cu-labeled anti-CD99 antibody. Clin Cancer Res 2014; 20:678-87. PubMed
  • Wang H, Zang C, Taing L, Arnett KL, Wong YJ, Pear WS, Blacklow SC, Liu XS, Aster JC. NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc Natl Acad Sci U S A 2014; 111:705-10. PubMed
  • Andrawes MB, Xu X, Liu H, Ficarro SB, Marto JA, Aster JC, Blacklow SC. Intrinsic selectivity of Notch 1 for Delta-like 4 over Delta-like 1. J Biol Chem 2013; 288:25477-89. PubMed
  • Ngondo-Mbongo RP, Myslinski E, Aster JC, Carbon P. Modulation of gene expression via overlapping binding sites exerted by ZNF143, Notch1 and THAP11. Nucleic Acids Res 2013; 41:4000-14. PubMed
  • Roti G, Carlton A, Ross KN, Markstein M, Pajcini K, Su AH, Perrimon N, Pear WS, Kung AL, Blacklow SC, Aster JC, Stegmaier K. Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 2013; 23:390-405. PubMed
  • Aster JC, DeAngelo DJ. Resistance revealed in acute lymphoblastic leukemia. Nat Med 2013; 19:264-5. PubMed
  • Kluk MJ, Ashworth T, Wang H, Knoechel B, Mason EF, Morgan EA, Dorfman D, Pinkus G, Weigert O, Hornick JL, Chirieac LR, Hirsch M, Oh DJ, South AP, Leigh IM, Pourreyron C, Cassidy AJ, Deangelo DJ, Weinstock DM, Krop IE, Dillon D, Brock JE, Lazar AJ, Peto M, Cho RJ, Stoeck A, Haines BB, Sathayanrayanan S, Rodig S, Aster JC. Gauging NOTCH1 Activation in Cancer Using Immunohistochemistry. PLoS ONE 2013; 8:e67306. PubMed
  • Giambra V, Jenkins CR, Wang H, Lam SH, Shevchuk OO, Nemirovsky O, Wai C, Gusscott S, Chiang MY, Aster JC, Humphries RK, Eaves C, Weng AP. NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-慮 and reactive oxygen species. Nat Med 2012; 18:1693-8. PubMed
  • Chiang MY, Shestova O, Xu L, Aster JC, Pear WS. Divergent effects of supraphysiological Notch signals on leukemia stem cells and hematopoietic stem cells. Blood 2012. PubMed
  • McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS, Chin KT, Partridge JC, Poole BB, Cheng KH, Daggett J, Cullen K, Kantoff E, Hasselbatt K, Berkowitz J, Muto MG, Berkowitz RS, Aster JC, Matulonis UA, Dinulescu DM. Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci U S A 2012; 109:E2939-48. PubMed
  • Tan MJ, White EA, Sowa ME, Harper JW, Aster JC, Howley PM. Cutaneous 硫-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling. Proc Natl Acad Sci U S A 2012; 109:E1473-80. PubMed
  • Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, West NH, Agoston ES, Reynoird N, Khochbin S, Ince TA, Christie A, Janeway KA, Vargas SO, Perez-Atayde AR, Aster JC, Sallan SE, Kung AL, Bradner JE, French CA. Differentiation of NUT Midline Carcinoma by Epigenomic Reprogramming. Cancer Res 2011; 71:2686-96. PubMed
  • Van de Walle I, De Smet G, Gärtner M, De Smedt M, Waegemans E, Vandekerckhove B, Leclercq G, Plum J, Aster JC, Bernstein ID, Guidos CJ, Kyewski B, Taghon T. Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. Blood 2011. PubMed
  • Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature 2011; 471:104-9. PubMed
  • Aster JC, Blacklow SC, Pear WS. Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J Pathol 2010; 223:262-73. PubMed
  • Ashworth TD, Pear WS, Chiang MY, Blacklow SC, Mastio J, Xu L, Kelliher M, Kastner P, Chan S, Aster JC. Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. Blood 2010; 116:5455-64. PubMed
  • Jeannet R, Mastio J, Macias-Garcia A, Oravecz A, Ashworth T, Geimer Le Lay AS, Jost B, Le Gras S, Ghysdael J, Gridley T, Honjo T, Radtke F, Aster JC, Chan S, Kastner P. Oncogenic activation of the Notch1 gene by deletion of its promoter in Ikaros-deficient T-ALL. Blood 2010; 116:5443-54. PubMed
  • Roper N, Deangelo DJ, Kuo F, Cin PD, Ghobrial I, Aster JC. An asymptomatic 61-year-old man with BCR-ABL-positive bone marrow following autologous transplantation for multiple myeloma. Am J Hematol 2010; 85:944-6. PubMed
  • Bertrand KA, Birmann BM, Chang ET, Spiegelman D, Aster JC, Zhang SM, Laden F. A prospective study of Epstein-Barr virus antibodies and risk of non-Hodgkin lymphoma. Blood 2010; 116:3547-53. PubMed
  • Arnett KL, Hass M, McArthur DG, Ilagan MX, Aster JC, Kopan R, Blacklow SC. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat Struct Mol Biol 2010; 17:1312-7. PubMed
  • Liu H, Chi AW, Arnett KL, Chiang MY, Xu L, Shestova O, Wang H, Li YM, Bhandoola A, Aster JC, Blacklow SC, Pear WS. Notch dimerization is required for leukemogenesis and T-cell development. Genes Dev 2010; 24:2395-407. PubMed
  • Laden F, Bertrand KA, Altshul L, Aster JC, Korrick SA, Sagiv SK. Plasma organochlorine levels and risk of non-Hodgkin lymphoma in the Nurses' Health Study. Cancer Epidemiol Biomarkers Prev 2010; 19:1381-4. PubMed
  • Mazzone M, Selfors LM, Albeck J, Overholtzer M, Sale S, Carroll DL, Pandya D, Lu Y, Mills GB, Aster JC, Artavanis-Tsakonas S, Brugge JS. Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci U S A 2010; 107:5012-7. PubMed
  • Bertrand KA, Spiegelman D, Aster JC, Altshul LM, Korrick SA, Rodig SJ, Zhang SM, Kurth T, Laden F. Plasma organochlorine levels and risk of non-Hodgkin lymphoma in a cohort of men. Epidemiology 2010; 21:172-80. PubMed
  • Dal Cin P, Aster JC, DeAngelo DJ. When to go FISHing. Am J Clin Pathol 2010; 133:351-3. PubMed
  • Lin YW, Beharry ZM, Hill EG, Song JH, Wang W, Xia Z, Zhang Z, Aplan PD, Aster JC, Smith CD, Kraft AS. A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood 2010; 115:824-33. PubMed
  • Yoda A, Yoda Y, Chiaretti S, Bar-Natan M, Mani K, Rodig SJ, West N, Xiao Y, Brown JR, Mitsiades C, Sattler M, Kutok JL, DeAngelo DJ, Wadleigh M, Piciocchi A, Dal Cin P, Bradner JE, Griffin JD, Anderson KC, Stone RM, Ritz J, Foà R, Aster JC, Frank DA, Weinstock DM. Functional screening identifies CRLF2 in precursor B-cell acute lymphoblastic leukemia. Proc Natl Acad Sci U S A 2010; 107:252-7. PubMed
  • Aste-Amézaga M, Zhang N, Lineberger JE, Arnold BA, Toner TJ, Gu M, Huang L, Vitelli S, Vo KT, Haytko P, Zhao JZ, Baleydier F, L'Heureux S, Wang H, Gordon WR, Thoryk E, Andrawes MB, Tiyanont K, Stegmaier K, Roti G, Ross KN, Franlin LL, Wang H, Wang F, Chastain M, Bett AJ, Audoly LP, Aster JC, Blacklow SC, Huber HE. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS ONE 2010; 5:e9094. PubMed
  • Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE. Direct inhibition of the NOTCH transcription factor complex. Nature 2009; 462:182-8. PubMed
  • Haack H,Johnson LA,Fry CJ,Crosby K,Polakiewicz RD,Stelow EB,Hong SM,Schwartz BE,Cameron MJ,Rubin MA,Chang MC,Aster JC,French CA. Diagnosis of NUT Midline Carcinoma Using a NUT-specific Monoclonal Antibody. Am J Surg Pathol 2009; 33:984-91. PubMed
  • Aster JC. Notch targeting 2.0. Blood 2009; 113:6044-5. PubMed
  • Gordon WR,Roy M,Vardar-Ulu D,Garfinkel M,Mansour MR,Aster JC,Blacklow SC. Structure of the Notch1-negative regulatory region: implications for normal activation and pathogenic signaling in T-ALL. Blood 2008; 113:4381-90. PubMed
  • Cornejo MG,Kharas MG,Werneck MB,Le Bras S,Moore SA,Ball B,Beylot-Barry M,Rodig SJ,Aster JC,Lee BH,Cantor H,Merlio JP,Gilliland DG,Mercher T. Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood 2009; 113:2746-54. PubMed
  • Joshi I,Minter LM,Telfer J,Demarest RM,Capobianco AJ,Aster JC,Sicinski P,Fauq A,Golde TE,Osborne BA. Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases. Blood 2008; 113:1689-98. PubMed
  • Gordon WR, Vardar-Ulu D, L'Heureux S, Ashworth T, Malecki MJ, Sanchez-Irizarry C, McArthur DG, Histen G, Mitchell JL, Aster JC, Blacklow SC. Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS ONE 2009; 4:e6613. PubMed
  • Poitras JL,Dal Cin P,Aster JC,Deangelo DJ,Morton CC. Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. Genes Chromosomes Cancer 2008; 47:884-9. PubMed
  • Mercher T,Cornejo MG,Sears C,Kindler T,Moore SA,Maillard I,Pear WS,Aster JC,Gilliland DG. Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell 2008; 3:314-26. PubMed
  • Chiang MY,Xu L,Shestova O,Histen G,L'heureux S,Romany C,Childs ME,Gimotty PA,Aster JC,Pear WS. Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia. J Clin Invest 2008; 118:3181-94. PubMed
  • Stelow EB, Bellizzi AM, Taneja K, Mills SE, Legallo RD, Kutok JL, Aster JC, French CA. NUT Rearrangement in Undifferentiated Carcinomas of the Upper Aerodigestive Tract. Am J Surg Pathol 2008; 32:828-34. PubMed
  • Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, Pross SE, Aster JC, Bhandoola A, Radtke F, Pear WS. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2008; 2:356-66. PubMed
  • French CA, Ramirez CL, Kolmakova J, Hickman TT, Cameron MJ, Thyne ME, Kutok JL, Toretsky JA, Tadavarthy AK, Kees UR, Fletcher JA, Aster JC. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 2008; 27:2237-42. PubMed
  • Li K, Li Y, Wu W, Gordon WR, Chang DW, Lu M, Scoggin S, Fu T, Vien L, Histen G, Zheng J, Martin-Hollister R, Duensing T, Singh S, Blacklow SC, Yao Z, Aster JC, Zhou BB. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem 2008; 283:8046-54. PubMed
  • Del Bianco C, Aster JC, Blacklow SC. Mutational and energetic studies of Notch 1 transcription complexes. J Mol Biol 2007; 376:131-40. PubMed
  • Rodig SJ, Payne EG, Degar BA, Rollins B, Feldman AL, Jaffe ES, Androkites A, Silverman LB, Longtine JA, Kutok JL, Fleming MD, Aster JC. Aggressive Langerhans cell histiocytosis following T-ALL: clonally related neoplasms with persistent expression of constitutively active NOTCH1. Am J Hematol 2007; 83:116-21. PubMed
  • Takeyama K, Monti S, Manis JP, Cin PD, Getz G, Beroukhim R, Dutt S, Aster JC, Alt FW, Golub TR, Shipp MA. Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. Oncogene 2008; 27:318-22. PubMed
  • Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu Rev Pathol 2007; 3:587-613. PubMed
  • Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. Notch signals positively regulate activity of the mTOR pathway in T cell acute lymphoblastic leukemia. Blood 2007; 110:278-86. PubMed
  • Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A, O'Neil J, Gutierrez A, Ivanova E, Perna I, Lin E, Mani V, Jiang S, McNamara K, Zaghlul S, Edkins S, Stevens C, Brennan C, Martin ES, Wiedemeyer R, Kabbarah O, Nogueira C, Histen G, Aster J, Mansour M, Duke V, Foroni L, Fielding AK, Goldstone AH, Rowe JM, Wang YA, Look AT, Stratton MR, Chin L, Futreal PA, DePinho RA. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 2007; 447:966-71. PubMed
  • Fung E, Tang SM, Canner JP, Morishige K, Arboleda-Velasquez JF, Cardoso AA, Carlesso N, Aster JC, Aikawa M. Delta-Like 4 Induces Notch Signaling in Macrophages. Implications for Inflammation. Circulation 2007; 115:2948-56. PubMed
  • Robertson MJ, Kahl BS, Vose JM, de Vos S, Laughlin M, Flynn PJ, Rowland K, Cruz JC, Goldberg SL, Musib L, Darstein C, Enas N, Kutok JL, Aster JC, Neuberg D, Savage KJ, LaCasce A, Thornton D, Slapak CA, Shipp MA. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2007; 25:1741-6. PubMed
  • Gordon WR, Vardar-Ulu D, Histen G, Sanchez-Irizarry C, Aster JC, Blacklow SC. Structural basis for autoinhibition of Notch. Nat Struct Mol Biol 2007; 14:295-300. PubMed
  • Chen J, Jette C, Kanki JP, Aster JC, Look AT, Griffin JD. NOTCH1-induced T-cell leukemia in transgenic zebrafish. Leukemia 2007; 21:462-71. PubMed
  • Nam Y, Sliz P, Pear WS, Aster JC, Blacklow SC. Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc Natl Acad Sci U S A 2007; 104:2103-8. PubMed
  • Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet Dev 2006; 17:52-9. PubMed
  • Shepard JL, Amatruda JF, Finkelstein D, Ziai J, Finley KR, Stern HM, Chiang K, Hersey C, Barut B, Freeman JL, Lee C, Glickman JN, Kutok JL, Aster JC, Zon LI. A mutation in separase causes genome instability and increased susceptibility to epithelial cancer. Genes Dev 2007; 21:55-9. PubMed
  • Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 2006; 103:18261-6. PubMed
  • Keeshan K, He Y, Wouters BJ, Shestova O, Xu L, Sai H, Rodriguez CG, Maillard I, Tobias JW, Valk P, Carroll M, Aster JC, Delwel R, Pear WS. Tribbles homolog 2 inactivates C/EBPalpha and causes acute myelogenous leukemia. Cancer Cell 2006; 10:401-11. PubMed
  • Palomero T, McKenna K, O-Neil J, Galinsky I, Stone R, Suzukawa K, Stiakaki E, Kalmanti M, Fox EA, Caligiuri MA, Aster JC, Look AT, Ferrando AA. Activating mutations in NOTCH1 in acute myeloid leukemia and lineage switch leukemias. Leukemia 2006; 20:1963-6. PubMed
  • Chen A, Zhao B, Kieff E, Aster JC, Wang F. EBNA-3B- and EBNA-3C-regulated cellular genes in Epstein-Barr virus-immortalized lymphoblastoid cell lines. J Virol 2006; 80:10139-50. PubMed
  • Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC. Identification of a Conserved Negative Regulatory Sequence That Influences the Leukemogenic Activity of NOTCH1. Mol Cell Biol 2006; 26:6261-71. PubMed
  • Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006; 20:2096-109. PubMed
  • van Vlierberghe P, Meijerink JP, Lee C, Ferrando AA, Look AT, van Wering ER, Beverloo HB, Aster JC, Pieters R. A new recurrent 9q34 duplication in pediatric T-cell acute lymphoblastic leukemia. Leukemia 2006; 20:1245-53. PubMed
  • Malecki MJ, Sanchez-Irizarry C, Mitchell JL, Histen G, Xu ML, Aster JC, Blacklow SC. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol 2006; 26:4642-51. PubMed
  • Takahashi H, Feuerhake F, Kutok JL, Monti S, Dal Cin P, Neuberg D, Aster JC, Shipp MA. FAS death domain deletions and cellular FADD-like interleukin 1beta converting enzyme inhibitory protein (long) overexpression: alternative mechanisms for deregulating the extrinsic apoptotic pathway in diffuse large B-cell lymphoma subtypes. Clin Cancer Res 2006; 12:3265-71. PubMed
  • Bilello JP, Lang SM, Wang F, Aster JC, Desrosiers RC. Infection and persistence of rhesus monkey rhadinovirus in immortalized B-cell lines. J Virol 2006; 80:3644-9. PubMed
  • Nam Y, Sliz P, Song L, Aster JC, Blacklow SC. Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 2006; 124:973-83. PubMed
  • Pasqualucci L, Compagno M, Houldsworth J, Monti S, Grunn A, Nandula SV, Aster JC, Murty VV, Shipp MA, Dalla-Favera R. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J Exp Med 2006; 203:311-7. PubMed
  • O'neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, Alt FW, Kelliher M, Look AT. Activating Notch1 mutations in mouse models of T-ALL. Blood 2006; 107:781-5. PubMed
  • Takahashi H, Feuerhake F, Monti S, Kutok JL, Aster JC, Shipp MA. Lack of IKBA coding region mutations in primary mediastinal large B-cell lymphoma and the host response subtype of diffuse large B-cell lymphoma. Blood 2006; 107:844-5. PubMed
  • Bismar TA, Demichelis F, Riva A, Kim R, Varambally S, He L, Kutok J, Aster JC, Tang J, Kuefer R, Hofer MD, Febbo PG, Chinnaiyan AM, Rubin MA. Defining aggressive prostate cancer using a 12-gene model. Neoplasia 2006; 8:59-68. PubMed
  • Aster JC. Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities. Int J Hematol 2005; 82:295-301. PubMed
  • Shepard JL, Amatruda JF, Stern HM, Subramanian A, Finkelstein D, Ziai J, Finley KR, Pfaff KL, Hersey C, Zhou Y, Barut B, Freedman M, Lee C, Spitsbergen J, Neuberg D, Weber G, Golub TR, Glickman JN, Kutok JL, Aster JC, Zon LI. A zebrafish bmyb mutation causes genome instability and increased cancer susceptibility. Proc Natl Acad Sci U S A 2005; 102:13194-9. PubMed
  • Feuerhake F, Kutok JL, Monti S, Chen W, Lacasce AS, Cattoretti G, Kurtin P, Pinkus GS, de Leval L, Harris NL, Savage KJ, Neuberg D, Habermann TM, Dalla-Favera R, Golub TR, Aster JC, Shipp MA. NF{kappa}B activity, function and target gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood 2005; 106:1392-9. PubMed
  • Sambandam A, Maillard I, Zediak VP, Xu L, Gerstein RM, Aster JC, Pear WS, Bhandoola A. Notch signaling controls the generation and differentiation of early T lineage progenitors. Nat Immunol 2005; 6:663-70. PubMed
  • Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, Shipp MA. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2004; 105:1851-61. PubMed
  • Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, Berghmans S, Mayhall EA, Traver D, Fletcher CD, Aster JC, Granter SR, Look AT, Lee C, Fisher DE, Zon LI. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol 2005; 15:249-54. PubMed
  • Rodig SJ, Savage KJ, Nguyen V, Pinkus GS, Shipp MA, Aster JC, Kutok JL. TRAF1 expression and c-Rel activation are useful adjuncts in distinguishing classical Hodgkin lymphoma from a subset of morphologically or immunophenotypically similar lymphomas. Am J Surg Pathol 2005; 29:196-203. PubMed
  • Sanchez-Irizarry C, Carpenter AC, Weng AP, Pear WS, Aster JC, Blacklow SC. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats. Mol Cell Biol 2004; 24:9265-73. PubMed
  • Pear WS, Aster JC. T cell acute lymphoblastic leukemia/lymphoma: a human cancer commonly associated with aberrant NOTCH1 signaling. Curr Opin Hematol 2004; 11:426-33. PubMed
  • Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306:269-71. PubMed
  • Maillard I, Weng AP, Carpenter AC, Rodriguez CG, Sai H, Xu L, Allman D, Aster JC, Pear WS. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 2004; 104:1696-702. PubMed
  • Rivailler P, Carville A, Kaur A, Rao P, Quink C, Kutok JL, Westmoreland S, Klumpp S, Simon M, Aster JC, Wang F. Experimental Rhesus Lymphocryptovirus Infection in Immunosuppressed Macaques: An Animal Model for Epstein-Barr Virus Pathogenesis in the Immunosuppressed Host. Blood 2004; 104:1482-9. PubMed
  • Das I, Craig C, Funahashi Y, Jung KM, Kim TW, Byers R, Weng AP, Kutok JL, Aster JC, Kitajewski J. Notch oncoproteins depend on gamma-secretase/presenilin activity for processing and function. J Biol Chem 2004; 279:30771-80. PubMed
  • Kutok JL, Klumpp S, Simon M, MacKey JJ, Nguyen V, Middeldorp JM, Aster JC, Wang F. Molecular evidence for rhesus lymphocryptovirus infection of epithelial cells in immunosuppressed rhesus macaques. J Virol 2004; 78:3455-61. PubMed
  • Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 2004; 14:48-54. PubMed
  • Weng AP, Aster JC. No T without D3: a critical role for cyclin D3 in normal and malignant precursor T cells. Cancer Cell 2004; 4:417-8. PubMed
  • Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, Kurtin P, Dal Cin P, Ladd C, Feuerhake F, Aguiar RC, Li S, Salles G, Berger F, Jing W, Pinkus GS, Habermann T, Dalla-Favera R, Harris NL, Aster JC, Golub TR, Shipp MA. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 2003; 102:3871-9. PubMed
  • Wilkinson K, Velloso ER, Lopes LF, Lee C, Aster JC, Shipp MA, Aguiar RC. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood 2003; 102:4187-90. PubMed
  • Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, Takeda Y, Chia W, Sankar N, Ng YK, Ling EA, Maciag T, Small D, Trifonova R, Kopan R, Okano H, Nakafuku M, Chiba S, Hirai H, Aster JC, Schachner M, Pallen CJ, Watanabe K, Xiao ZC. F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 2003; 115:163-75. PubMed
  • Vardar D, North CL, Sanchez-Irizarry C, Aster JC, Blacklow SC. Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1. Biochemistry 2003; 42:7061-7. PubMed
  • Takeyama K, Aguiar RC, Gu L, He C, Freeman GJ, Kutok JL, Aster JC, Shipp MA. The BAL-binding protein BBAP and related Deltex family members exhibit ubiquitin-protein isopeptide ligase activity. J Biol Chem 2003; 278:21930-7. PubMed
  • Nam Y, Weng AP, Aster JC, Blacklow SC. Structural requirements for assembly of the CSL.intracellular Notch1.Mastermind-like 1 transcriptional activation complex. J Biol Chem 2003; 278:21232-9. PubMed
  • Langenau DM, Traver D, Ferrando AA, Kutok JL, Aster JC, Kanki JP, Lin S, Prochownik E, Trede NS, Zon LI, Look AT. Myc-induced T cell leukemia in transgenic zebrafish. Science 2003; 299:887-90. PubMed
  • Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, Aster JC. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003; 23:655-64. PubMed
  • Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM, Miele L. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 2002; 8:979-86. PubMed
  • Kutok JL, Aster JC. Molecular biology of anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma. J Clin Oncol 2002; 20:3691-702. PubMed
  • Nam Y, Aster JC, Blacklow SC. Notch signaling as a therapeutic target. Curr Opin Chem Biol 2002; 6:501-9. PubMed
  • Million RP, Aster J, Gilliland DG, Van Etten RA. The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice. Blood 2002; 99:4568-77. PubMed
  • Izon DJ, Aster JC, He Y, Weng A, Karnell FG, Patriub V, Xu L, Bakkour S, Rodriguez C, Allman D, Pear WS. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 2002; 16:231-43. PubMed
  • Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, Gaasenbeek M, Angelo M, Reich M, Pinkus GS, Ray TS, Koval MA, Last KW, Norton A, Lister TA, Mesirov J, Neuberg DS, Lander ES, Aster JC, Golub TR. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002; 8:68-74. PubMed
  • Andreasson P, Schwaller J, Anastasiadou E, Aster J, Gilliland DG. The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo. Cancer Genet Cytogenet 2001; 130:93-104. PubMed
  • Allman D, Karnell FG, Punt JA, Bakkour S, Xu L, Myung P, Koretzky GA, Pui JC, Aster JC, Pear WS. Separation of Notch1 promoted lineage commitment and expansion/transformation in developing T cells. J Exp Med 2001; 194:99-106. PubMed
  • Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, Oh H, Aster JC, Krishna S, Metzger D, Chambon P, Miele L, Aguet M, Radtke F, Dotto GP. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 2001; 20:3427-36. PubMed
  • Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000; 26:484-9. PubMed
  • Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol Cell Biol 2000; 20:7505-15. PubMed
  • Schwaller J, Parganas E, Wang D, Cain D, Aster JC, Williams IR, Lee CK, Gerthner R, Kitamura T, Frantsve J, Anastasiadou E, Loh ML, Levy DE, Ihle JN, Gilliland DG. Stat5 is essential for the myelo- and lymphoproliferative disease induced by TEL/JAK2. Mol Cell 2000; 6:693-704. PubMed
  • Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Kimberly WT, Weinmaster G, Selkoe DJ, Hyman BT. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J Neurochem 2000; 75:583-93. PubMed
  • Xiao S, McCarthy JG, Aster JC, Fletcher JA. ZNF198-FGFR1 transforming activity depends on a novel proline-rich ZNF198 oligomerization domain. Blood 2000; 96:699-704. PubMed
  • Liu Q, Schwaller J, Kutok J, Cain D, Aster JC, Williams IR, Gilliland DG. Signal transduction and transforming properties of the TEL-TRKC fusions associated with t(12;15)(p13;q25) in congenital fibrosarcoma and acute myelogenous leukemia. EMBO J 2000; 19:1827-38. PubMed
  • Rand MD, Grimm LM, Artavanis-Tsakonas S, Patriub V, Blacklow SC, Sklar J, Aster JC. Calcium depletion dissociates and activates heterodimeric notch receptors. Mol Cell Biol 2000; 20:1825-35. PubMed
  • Tomasson MH, Sternberg DW, Williams IR, Carroll M, Cain D, Aster JC, Ilaria RL, Van Etten RA, Gilliland DG. Fatal myeloproliferation, induced in mice by TEL/PDGFbetaR expression, depends on PDGFbetaR tyrosines 579/581. J Clin Invest 2000; 105:423-32. PubMed
  • Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner J. Direct inhibition of the Notch transcription factor complex Nature 2009.
  • Aster JC, Simms WB, Zavala-Ruiz Z, Patriub V, North CL, Blacklow SC. The folding and structural integrity of the first LIN-12 module of human Notch1 are calcium-dependent. Biochemistry 1999; 38:4736-42. PubMed
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