Research Program

My research program focuses on the pathogenesis of lymphoid malignancy and entails two major arms. First, we have explored the role of NOTCH1 and other oncogenes/tumor suppressors in the genesis and propagation of T-cell acute lymphoblastic leukemia (T-ALL) including studies on downstream target genes/pathways and identifying mechanisms operative in leukemia stem cells. We have addressed these questions in cells from different developmental stages and tissue contexts on the hypothesis that preset epigenetic programs may restrict the oncogenic trajectories available to the cells as they undergo the initial stages of transformation and clonal establishment. Many of our findings have direct clinical relevance in that they serve as basis for the development of rational therapies that target disease-specific phenotypes.

As a second and more recent focus, my lab has explored the use of state-of-the-art mass cytometry (CyTOF) to obtain highly resolved phenotypic maps of heterogeneous cell populations in present in patient lymphoma biopsy samples including both malignant and reactive immune cell compartments. We have used this methodology to characterize intratumoral heterogeneity/subclonal diversity among malignant cell populations and stereotyped or patient-specific immune responses. This work is also of direct clinical relevance in providing detailed phenotypic characterizations that are required in order to define biomarkers for lymphoma classification and prognosis, and monitoring of patient-specific responses to therapy.

Specific projects include:

1) Pathogenetic mechanisms in T-ALL. Using our recently developed cord blood transduction approach, we are able to generate synthetic T-ALL by de novo transformation of normal human hematopoietic progenitors with activated NOTCH1 in combination with accessory oncogenes (M. Kusakabe et al, manuscript in preparation). This model produces clonal T-ALL populations in vitro within 2 months, or clonal T-ALL disease in mice within 3 months. Using this model, we are actively exploring the following areas:

1. Epigenetic patterning in human T-ALL. We are characterizing the initial establishment and propagation of epigenetic patterns that direct the process of malignant transformation and clonal establishment. We are performing these studies in collaboration with Martin Hirst at UBC.
2. Collaborating pathogenetic pathways in human T-ALL. We are executing shRNA and sgRNA screens to identify functional pathways required for clonal establishment and propagation.
3. Cell-of-origin dependent programs T-ALL. By varying the input cell source, we are testing whether distinct types of T-ALL are generated from hematopoietic progenitors derived from cord blood vs. fetal liver vs. post-natal thymus vs. adult bone marrow. We have also done considerable work in this area using mouse tissues, comparing fetal liver and adult bone marrow, and revealed developmental stage-specific induction of autocrine growth factor signaling pathways (V. Giambra et al, manuscript in preparation).
4. Clonal heterogeneity in human T-ALL. Using a cellular barcoding approach, we are exploring clonal dynamics during tumor establishment and propagation. We are performing this work in collaboration with Connie Eaves at BCCA.

*This work is currently funded by a Terry Fox Research Institute Program Project Grant (2017-2022).

2) Leukemia stem cells in T-ALL. We are continuing our work examining the roles of PKCθ and Wnt signaling in maintaining leukemia stem cell activity in this disease. In the PKCθ project, we have taken a biochemical approach to dissecting downstream pathways. We developed an analog-specific kinase variant of PKCθ, followed by discovery mode mass spectrometry (LC-ESI-MS/MS) to define direct kinase targets, and are pursuing functional validation of hits. This work is being done in collaboration with Gregg Morin at BCCA.

In the Wnt project, we are utilizing our integrated, real-time fluorescent Wnt reporter construct which labels a population of Wnt-active cells that is highly enriched for leukemia-initiating cell (LIC) activity, to define gene expression programs unique to leukemia stem cells. We are also dissecting the structural elements required for activating downstream gene expression programs using conditional Lef1 and Tcf7 mice obtained in collaboration with Howard Xue at the University of Iowa. We are also starting to extend this work into our synthetic human T-ALL model and in our sizable panel of patient-derived xenografts (PDX).

*This work is currently funded by a Canadian Institutes of Health Research (CIHR) Project Scheme operating grant (2016-2021).

3) Tumor ecosystem in human lymphoma. We are using mass cytometry (CyTOF) paired with single cell genomics approaches to characterize both inter- and intra-tumoral heterogeneity in human B-cell lymphomas. We are examining malignant B cell populations as well as infiltrating immune cell populations (predominantly T-cells). We are focusing this work on two common types of lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. We access clinical specimens from the prodigious lymphoma tumor bank established at BCCA. We are performing these studies in collaboration with Sohrab Shah, Christian Steidl, and David Scott at BCCA.

*This project is currently funded by a Canadian Institutes of Health Research (CIHR) Project Scheme operating grant (2016-2021), and a Terry Fox Research Institute Program Project Grant (2016-2021).

Updated March, 2018

Currently Established Methodologies and Approaches

Animal models of leukemia/lymphoma including :

• Transgenic VavP-Bcl2 and IGF1Rneo (hypomorphic allele)
• Conditional (loxP/Cre) alleles for Cdkn2a, Prkcq, Runx1, Cbfb, Ctnnb1, Tcf7, and Lef1
• Viral transduction/bone marrow transplantation model

Xenograft animal models of leukemia including:

• Patient-derived xenograft models (16 lines established in the lab, access to an additional 10 by reciprocal agreement with other T-ALL labs)
• Synthetic human T-ALL generated by viral transduction/transplantation of human fetal liver, cord blood, post natal thymus, and adult bone marrow

Currently we use NSG as our standard immunodeficient recipients, but are currently testing other variants including human cytokine knock-ins/transgenics to support improved engraftment/propagation of human cells.

Cell culture models of leukemia/lymphoma including:

• Established human cell lines (~30 T-ALL and 10 DLBCL cell lines, all STR validated) and others including stromal feeders (OP9-DL1, OP9-DL4, MS5-DL1) and standard general use lines (293T, 3T3, U20S, HeLa, etc).
• PDX lines cultured on stromal feeders in defined serum-free media (Yost et al, Leukemia 2015).
• Primary cultures of virally-transduced human HSPC cultured on stromal feeders.
• In vitro adapted primary mouse leukemias.

Access to primary human lymphoma specimens:

I am Director of the BCCA Clinical Flow Cytometry Lab and co-manage the Lymphoma Tumor Repository with Drs. Christian Steidl and David Scott. The clinical flow lab accessions nearly 4,000 specimens each year for assessment of lymphoproliferative disease (LPD) including representative portions of ~1,000 excisional lymph node (LN) biopsies. Among these, approximately 100 per year represent follicular lymphoma (FL) and another 100 per year represent diffuse large B cell lymphoma (DLBCL). Single cell suspensions are generated by manual disaggregation and processed for flow cytometric phenotyping using our routine 13-color clinical assay (BD LSRFortessa platform). After diagnostic testing is completed, there are often several to tens of millions of excess viable cells remaining which are prospectively banked with DMSO cryoprotectant. This has been going on for over 2 decades as part of the well established BCCA Lymphoma Program. There are currently over 1,300 cases each of FL and DLBCL in the tumor bank, as well as abundant reactive (normal) lymph nodes to serve as a source of normal control material.

Gene transduction/editing approaches:

• Pseudotyped lentiviral vectors including use of multicistronic picornaviral 2A cassettes and fluorescent/epitope tags including GFP, YFP, mCherry, tNGFR, mCD8, hCD4, and hCD8
• Lentiviral shRNA library screening
• CRISPR/Cas9 ribonucleoprotein-mediated gene editing

Other methods:

• High parameter conventional flow cytometry, mass cytometry (CyTOF)
• qRT-PCR, droplet digital PCR (Bio-Rad QX200)
• Wes^TM western blotting
• Ascorbate peroxidase (APEX)-generated molecular labeling
• Analog-specific kinases (à la Kevan Shokat, in collaboration with Gregg Morin)

Omics Approaches:

• Whole exome sequencing, targeted amplicon sequencing (in collaboration with Christian Steidl at BCCA)
• RNA-seq (in collaboration with Martin Hirst at UBC)
• ChIP-seq (in collaboration with Martin Hirst at UBC)
• Nano-electrospray ionization tandem mass spectrometry (LC-MS/MS) (in collaboration with Gregg Morin at BCCA)

Updated Jan 13, 2016

Kusakabe M, Sun AC, Tyshchenko K, Wong R, Nanda A, Shanna C, Gusscott S, Chavez EA, Lorzadeh A, Zhu A, Hill A, Hung S, Brown S,  Babaian A, Wang X, Holt RA, Steidl C, Karsan A, Humphries RK, Eaves CJ, Hirst M, Weng AP. Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia. Nat Commun (In press, May 2019).

iambra V, Gusscott S, Gracias D, Song R, Lam SH, Panelli P, Tyshchenko K, Jenkins CE, Hoofd C, Lorzadeh A, Carles S, Hirst M, Eaves C,  Weng AP. Epigenetic Restoration of Fetal-like IGF1 Signaling Inhibits Leukemia Stem Cell Activity. Cell Stem Cell. Nov 1;23(5):714-726, 2018. View Abstract

Jenkins CE*, Gusscott S*, Wong RJ, Shevchuk OO, Rana G, Giambra V, Tyshchenko F, Islam R, Hirst M, & Weng AP.  RUNX1 promotes cell growth in human T-cell acute lymphoblastic leukemia by transcriptional regulation of key target genes.  Exp Hematol. Aug;64:84-96, 2018. *co-first authors View Abstract

Weiswald LB, Hasan MR, Wong JC, Pasiliao CC, Rahman M, Ren J, Yin Y, Gusscott S, Vacher S, Weng AP, Kennecke HF, Bièche I, Schaeffer DF, Yapp DT, Tai IT. Inactivation of the kinase domain of CDK10 prevents tumor growth in a preclinical model of colorectal cancer, and is accompanied by downregulation of Bcl-2. Mol Cancer Ther Oct;16(10):2292-2303, 2017. View Abstract 

Sasaki T, Rivera-Mulia JC, Vera D,  Zimmerman J, Das S, Padget M, Nakamichi N, Chang BH, Tyner J, Druker BJ, Weng AP, Civin CI, Eaves CJ, Gilbert DM. Stability of patient-specific features of altered DNA replication timing in xenografts of primary human acute lymphoblastic leukemia. Experimental Hematol 51:71-82.e3, 2017. View Abstract 

Yuan T, Yang Y, Chen J, Li W, Zhang Q, Mi Y, Goswami R, You J, Lin D, Qian MD, Calin S, Liang Y, Medeiros LJ, Miranda R, Calin G, Zhou X, Ma L, Liu B, Zweidler-McKay P, Weng A, Zhang Y, You Y. Regulation of PI3K signaling in T cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia Nov;31(11):2355-2364, 2017. View Abstract

Brown SD, Hapgood G, Steidl C, Weng AP, Savage KJ, Holt RA. Defining the clonality of peripheral T cell lymphomas using RNA-seq. Bioinformatics. 5;33(8):1111-1115, 2017. View Abstract

Gusscott S, Jenkins CE, Lam SH, Giambra V, Pollak M, Weng AP. IGF1R derived PI3K/AKT signaling maintains growth in a subset of human T-cell acute lymphoblastic leukemias. PLoS One. 11(8):e0161158, 2016. View Abstract

Stunnenberg HG, International Human Epigenome Consortium, Hirst M. The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. Cell 167 (5):1145-1149, 2016. (AP Weng is a member of the International Human Epigenome Consortium). View Abstract

Parker JDK, Shen Y, Pleasance E, Li Y, Schein JE, Zhao Y, Moore R, Wegrzyn-Woltosz J, Savage KJ, Weng AP, Gascoyne RD, Jones S, Marra M, Laskin J, Karsan A. Molecular etiology of an indolent lymphoproliferative disorder determined by whole-genome sequencing. Cold Spring Harb Mol Case Stud 2: a000679, 2016. View Abstract

Townsend EC, Murakami MA, Christodoulou A, Christie AL, Köster J, DeSouza TA, Morgan EA, Kallgren SP, Liu H, Wu SC, Plana O, Montero J, Stevenson KE, Rao P, Vadhi R, Andreeff M, Armand P, Ballen KK, Barzaghi-Rinaudo P, Cahill S, Clark RA, Cooke VG, Davids MS, DeAngelo DJ, Dorfman DM, Eaton H, Ebert BL, Etchin J, FirestoneGarnache B, Fisher DC, Freedman AS, Galinsky IA, Gao H, Garcia JS, Garnache-Ottou F, Graubert TA, Gutierrez A, Halilovic E, Harris MH, Herbert ZT, Horwitz SM, Inghirami G, Intlekoffer AM, Ito M, Izraeli S, Jacobsen ED, Jacobson CA, Jeay S, Jeremias I, Kelliher MA, Koch R, Konopleva M, Kopp N, Kornblau SM , Kung AL, Kupper TS, LaBoeuf N, LaCasce AS, Lees E, Li LS, Look AT, Murakami M, Muschen M, Neuberg D, Ng SY, Odejide OO, Orkin SH, Paquette RR, Place AE, Roderick JE, Ryan JA, Sallan SE, Shoji B, Silverman LB, Soiffer RJ, Steensma DP, Stegmaier K, Stone RM, Tamburini J, Thorner AR, van Hummelen P, Wadleigh M, Wiesmann M, Weng AP, Wuerthner JU, Williams DA, Wollison BM, Lane AA, Letai A, Bertagnolli MM, Ritz J, Brown M, Long H, Aster JC, Shipp MA, Griffin JD, Weinstock DM. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 29(4):574-86, 2016. View Abstract

Hoofd C, Wang X, Lam S, Jenkins C, Wood B, Giambra V*, Weng AP*.  CD44 promotes chemoresistance in T-ALL by increased drug efflux.  Exp Hematol. 44(3):166-171, 2016 (*equal contribution) View Abstract

Giambra V, Jenkins C, Lam SH, Hoofd C, Belmonte M, Wang X, Gusscott S, Gracias D & Weng AP.
Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling. Blood 125:3917-27, 2015.  View Abstract

Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB, Dastur A, Amzallag A, Ramaswamy S, Tesar B, Jenkins CE, Hannett NM, McMillin D, Sanda T, Sim T, Kim ND, Look T, Mitsiades CS, Weng AP, Brown JR, Benes CH, Marto JA, Young RA, Gray NS. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 511: 616-620, 2014. View Abstract

Gutierrez A, Pan L, Groen RWJ, 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. The Journal of Clinical Investigation 124: 644-655, 2014. View Abstract

Sanda T, Tyner JW, Gutierrez A, Ngo VN, Glover J, Chang BH, Yost A, Ma W, Fleischman AG, Zhou W, Yang Y, Kleppe M, Ahn Y, ., Tatarek J, Kelliher M, Neuberg D, Levine RL, Moriggl R, Muller M, Gray NS, Jamieson CH, Weng AP, Staudt LM, Druker BJ & Look T. TYK2-STAT1-BCL2 pathway dependence in T-Cell Acute Lymphoblastic Leukemia.  Cancer Discov 3: 564-577, 2013. View Abstract

Aghaeepour N, Finak G, the FlowCAP Consortium, the DREAM Consortium, Hoos H, Mosmann TR, Gottardo R, Brinkman RR & Scheuermann RH. Critical assessment of automated flow cytometry data analysis techniques. Nature Methods 10: 228-38, 2013 (Weng AP is a member of the FlowCAP Consortium). View Abstract

Yost AJ, Shevchuk OO, Gooch R, Gusscott S, You MJ, Ince TA*, Aster JC* & Weng AP*. Defined, serum-free conditions for in vitro culture of primary human T-ALL blasts. Leukemia 6: 1437-40, 2013 (* equal contribution).

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-q and reactive oxygen species.  Nat Med 18: 1693-8,  2012. (featured on the cover of the Nov 2012 issue) View Abstract

Jenkins CR, Shevchuk OO, Giambra V, Lam SH, Holzenberger M, Pollak M, Humphries RK & Weng AP. IGF signaling contributes to malignant transformation of hematopoietic progenitors by the MLL-AF9 oncoprotein. Exp Hematol 40:715-723, 2012. View Abstract

Gusscott S, Kuchenbauer F, Humphries RK & Weng AP. Notch-mediated repression of miR-223 contributes to IGF1R regulation in T-ALL. Leuk Res 36:905-11, 2012. View Abstract

Bashashati A, Johnson NA, Khodabakhshi AH, Whiteside MD, Zare H, Scott DW, Lo K, Gottardo R, Brinkman FSL, Connors JM, Slack GW, Gascoyne RD, Weng AP* & Brinkman RR* (*co-senior authors). B-cells with high side scatter parameter by flow cytometry correlate with inferior survival in diffuse large B cell lymphoma. Am J Clin Pathol 137: 805-814, 2012. View Abstract

Kridel R, Messner B, Rogic S, Boyle M, Telenius A, Woolcock B, Gunawardana J, Jenkins C, Cochrane C, Ben-Neriah S, Tan K, Opat S, Sehn LJ, Connors JM, Weng AP*, Steidl C* & Gascoyne RD* (*co-senior authors). Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119: 1963-1971, 2012. View Abstract

Zare H, Bashashati A, Kridel R, Aghaeepour N, Haffari G, Connors HM, Gupta A, Gascoyne RD, Brinkman RR* & Weng AP* (*co-senior authors). Automated analysis of multidimensional flow cytometry data improves diagnostic accuracy between mantle cell lymphoma and small lymphocytic lymphoma. Am J Clin Pathol 137:75-85, 2012. View Abstract

Dakappagari N, Ho SN, Gascoyne RD, Ranuio J, Weng AP*, Tangri S* (*co-senior authors). CD80 (B7.1) is expressed on both malignant B cells and non-malignant stromal cells in non-Hodgkin lymphoma. Cytometry B Clin Cytom 82: 112-119, 2012. View Abstract

Maddigan A, Truitt L, Arsenault R, Freywald T, Allonby O, Dean J, Narendran A, Xiang J, Weng A, Napper S, Freywald A. EphB receptors trigger Akt activation and suppress Fas receptor-incuced apoptosis in malignant T lymphocytes. J Immunol 187:5983-5994, 2011. View Abstract

Habibi D, Ogloff N, Jalili RB, Yost A, Weng AP, Ghahary A & Ong CJ. Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia.  Invest New Drugs 30:1361-70, 2012. View Abstract

Medyouf H, Gusscott S, Wang H, Tseng JC, Wai C, Nemirovsky O, Trumpp A, Pflumio F, Carboni J, Gottardis M, Pollak M, Kung AL, Aster JC, Holzenberger M, Weng AP. 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, 2011. (featured on the cover of Nov 2011 issue) View Abstract

Finak G, Perez J-M, Weng A & Gottardo R. Optimizing transformations for automated, high throughput analysis of flow cytometry data. BMC Bioinformatics 11: 546, 2010. View Abstract

Petriv OI, Kuchenbauer F, Delaney AD, Lecault V, White A, Kent D, Marmolejo L, Heuser M, Berg T, Copley M, Ruschmann J, Sekulovic S, Benz C, Kuroda E, Ho V, Antignano F, Halim T, Giambra V, Krystal G, Takei F, Weng AP, Piret J, Eaves C, Marra MA, Humphries RK & Hansen CL. Comprehensive microRNA expression profiling of the hematopoietic hierarchy. Proc Natl Acad Sci USA 107:15443-8, 2010. View Abstract

Medyouf H, Gao XH, Armstrong F, Gusscott S, Liu Q, Gedman AL, Matherly LH, Schultz KR, Pflumio F, You MJ & Weng AP. Acute T-cell leukemias remain dependent on notch signaling despite PTEN and INK4A/ARF loss.  Blood 115:1175-84, 2010. View Abstract

Hahne F*, Khodabakhshi AH*, Bashashati A, Wong C-J, Gascoyne RD, Weng AP, Seifert-Margolis S, Bourcier K, Asare A, Lumley T, Gentleman R & Brinkman RR. Per-channel basis normalization methods for flow cytometry data.  Cytometry A 77: 121-31, 2010. View Abstract

Heuser M, Sly LM, Argiropoulos B, Kuchenbauer F, Lai C, Weng A, Leung M, Lin G, Brookes C, Fung S, Valk PJ, Delvel R, Lowenberg B, Krystal G & Humphries RK. Modeling the functional heterogeneity of leukemia stem cells: Role of STAT5 in leukemia stem cell self-renewal. Blood, 114:3983-3993, 2009. View Abstract

Johnson NA, Boyle M, Bashashati A, Leach S, Brooks-Wilson A, Sehn LH, Chhanabhai M, Brinkman RR, Connors JM, Weng AP & Gascoyne RD. Diffuse large B cell lymphoma: reduced CD20 expression is associated with an inferior survival. Blood 113: 3773-80, 2009. View Abstract

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 110 (1): 278-86, 2007. View Abstract

Rodig SJ, Savage KJ, LaCasce AS, Weng AP, Harris NL, Shipp MA, Hsi ED, Gascoyne RD, & Kutok JL. Expression of TRAF1 and nuclear c-Rel distinguishes primary mediastinal large cell lymphoma from other types of diffuse large B-cell lymphoma. Am J Surg Pathol 31 (1): 106-12, 2007. View Abstract

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 103 (48): 18261-6, 2006. View Abstract

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 JC. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20 (15): 2096-109, 2006. View Abstract

Ringrose A, Zhou Y, Pang E, Zhou L, Lin AE, Sheng G, Li XJ, Weng A, Su MW, Pittelkow MR, & Jiang X. Evidence for an oncogenic role of AHI-1 in Sezary syndrome, a leukemic variant of human cutaneous T-cell lymphomas. Leukemia 20 (9): 1593-601, 2006. View Abstract

Weng AP, & Lau A. Notch signaling in T-cell acute lymphoblastic leukemia. Future Oncol 1 (4): 511-9, 2005. View Abstract

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 24 (21): 9265-73, 2004. View Abstract

Weng AP, Ferrando AA, Lee W, Morris JPt, Silverman LB, Sanchez-Irizarry C, Blacklow SC, Look AT, & Aster JC. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306 (5694): 269-71, 2004. View Abstract

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 104 (6): 1696-702, 2004. View Abstract

Lacasce A, Howard O, Lib S, Fisher D, Weng A, Neuberg D, & Shipp M. Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma 45 (4): 761-7, 2004. View Abstract

Brown JR, Weng AP, & Freedman AS. Hodgkin disease associated with T-cell non-Hodgkin lymphomas: case reports and review of the literature. Am J Clin Pathol 121 (5): 701-8, 2004. View Abstract

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 279 (29): 30771-80, 2004. View Abstract

Weng AP, & Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 14 (1): 48-54, 2004. View Abstract

Weng AP, & Aster JC. No T without D3: a critical role for cyclin D3 in normal and malignant precursor T cells. Cancer Cell 4 (6): 417-8, 2003. View Abstract

Dorfman DM, van den Elzen P, Weng AP, Shahsafaei A, & Glimcher LH. Differential expression of T-bet, a T-box transcription factor required for Th1 T-cell development, in peripheral T-cell lymphomas. Am J Clin Pathol 120 (6): 866-73, 2003. View Abstract

Weng AP, Shahsafaei A, & Dorfman DM. CXCR4/CD184 immunoreactivity in T-cell non-Hodgkin lymphomas with an overall Th1- Th2+ immunophenotype. Am J Clin Pathol 119 (3): 424-30, 2003. View Abstract

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 278 (23): 21232-9, 2003. View Abstract

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 23 (2): 655-64, 2003. View Abstract

Wohlschlegel JA, Kutok JL, Weng AP, & Dutta A. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Am J Pathol 161 (1): 267-73, 2002. View Abstract

Gaudet G, Friedberg JW, Weng A, Pinkus GS, & Freedman AS. Breast lymphoma associated with breast implants: two case-reports and a review of the literature. Leuk Lymphoma 43 (1): 115-9, 2002. View Abstract

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 16 (2): 231-43, 2002. View Abstract

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 8 (1): 68-74, 2002. View Abstract

Weng A, Magnuson T, & Storb U. Strain-specific transgene methylation occurs early in mouse development and can be recapitulated in embryonic stem cells. Development 121 (9): 2853-9, 1995. View Abstract

Weng A, Engler P, & Storb U. The bulk chromatin structure of a murine transgene does not vary with its transcriptional or DNA methylation status. Mol Cell Biol 15 (1): 572-9, 1995. View Abstract

Engler P, Weng A, & Storb U. Influence of CpG methylation and target spacing on V(D)J recombination in a transgenic substrate. Mol Cell Biol 13 (1): 571-7, 1993. View Abstract

Storb U, Engler P, Klotz E, Weng A, Haasch D, Pinkert C, Doglio L, Glymour M, & Brinster R. Rearrangement and expression of immunoglobulin genes in transgenic mice. Curr Top Microbiol Immunol 182: 137-41, 1992. View Abstract

Chensue SW, Shmyr-Forsch C, Weng A, Otterness IG, & Kunkel SL. Biologic and immunohistochemical analysis of macrophage interleukin- 1 alpha, - 1 beta, and tumor necrosis factor production during the peritoneal exudative response. J Leukoc Biol 46 (6): 529-37, 1989. View Abstract

The Weng lab currently has the following positions available:

Co-op (1 positions available) September 2019 – April 2020 (8 months)

Investigating the inter/intra-tumor heterogeneity in follicular lymphoma and diffuse large B-cell lymphoma and their accompanying reactive immune components. This project utilizes state-of-the-art single cell analysis (mass cytometry (CyTOF), single cell RNA sequencing), and variety of bioinformatics tools (high dimensional data analysis, machine learning, Bayesian statistics and some deep learning method such as variational auto encoder) . This work is of direct clinical relevance in providing detailed phenotypic characterizations that are required in order to define biomarkers for lymphoma classification and prognosis, and monitoring of patient-specific responses to therapy. In this position you will have opportunities to learn and practice on: 1) handling and processing clinical samples; 2) maintaining and operating the CyTOF and multi-parameter flow cytometry; 3) Multi-dimensional data analysis. We prefer applicants who are detail-oriented and have a strong interest in bioinformatics/programming as such skills will allow for more involvement in data analysis.  Applicants may apply via their school's co-op program.

Postdoctoral or Graduate student (ongoing)

The candidate will work on pathogenetic mechanisms in T-ALL and/or analysis of tumor ecosystem in human lymphoma by mass cytometry (CyTOF). Interested applicants may submit letter of interest and CV to aweng@bccrc.ca.