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.

Currently Established Methodologies and Approaches

  • Synthetic human models of leukemia/lymphoma
  • Conventional mouse models of leukemia/lymphoma
  • Patient-derived xenograft (PDX) models of leukemia
  • Access to clinically annotated primary human lymphoma specimens
  • Lentiviral gene transduction, CRISPR/Cas9 gene editing
  • RNA-seq, ChIP-seq, single cell RNA-seq, whole exome seq
  • High parameter flow cytometry (BD FACSymphony), mass cytometry (CyTOF)

Access to primary human lymphoma specimens

Dr. Weng is the Director of the BCCA Clinical Flow Cytometry Lab and co-manages 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.

 

 

 

Members

Faculty/Leaders

Staff

Post-Docs

Students/Trainees

Christopher Breden

Co-op student

Open Positions

Graduate / Postdoctoral

Ongoing recruitment.

Possible projects: Role of leukemia stem cells in T-ALL, examining the tumor ecosytem in lymphomas, or pathogenetic mechanisms in T-ALL.

Interested applicants may submit letter of interest and CV to aweng@bccrc.ca.

Co-op Position

1 positions available Jan 2020 – Aug 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.


The candidate will work on pathogenetic mechanisms in T-ALL and/or analysis of tumor ecosystem in human lymphoma by mass cytometry (CyTOF).

Please contact your university Co-op program to apply.  
 

Selected Publications

Probabilistic cell-type assignment of single-cell RNA-seq for tumor microenvironment profiling.

Nature methods, 2019
Zhang, Allen W, O'Flanagan, Ciara, Chavez, Elizabeth A, Lim, Jamie L P, Ceglia, Nicholas, McPherson, Andrew, Wiens, Matt, Walters, Pascale, Chan, Tim, Hewitson, Brittany, Lai, Daniel, Mottok, Anja, Sarkozy, Clementine, Chong, Lauren, Aoki, Tomohiro, Wang, Xuehai, Weng, Andrew P, McAlpine, Jessica N, Aparicio, Samuel, Steidl, Christian, Campbell, Kieran R, Shah, Sohrab P

Synthetic modeling reveals HOXB genes are critical for the initiation and maintenance of human leukemia.

Nature communications, 2019
Kusakabe, Manabu, Sun, Ann Chong, Tyshchenko, Kateryna, Wong, Rachel, Nanda, Aastha, Shanna, Claire, Gusscott, Samuel, Chavez, Elizabeth A, Lorzadeh, Alireza, Zhu, Alice, Hill, Ainsleigh, Hung, Stacy, Brown, Scott, Babaian, Artem, Wang, Xuehai, Holt, Robert A, Steidl, Christian, Karsan, Aly, Humphries, R Keith, Eaves, Connie J, Hirst, Martin, Weng, Andrew P

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Cancer cell, 2016
Townsend, Elizabeth C, Murakami, Mark A, Christodoulou, Alexandra, Christie, Amanda L, Köster, Johannes, DeSouza, Tiffany A, Morgan, Elizabeth A, Kallgren, Scott P, Liu, Huiyun, Wu, Shuo-Chieh, Plana, Olivia, Montero, Joan, Stevenson, Kristen E, Rao, Prakash, Vadhi, Raga, Andreeff, Michael, Armand, Philippe, Ballen, Karen K, Barzaghi-Rinaudo, Patrizia, Cahill, Sarah, Clark, Rachael A, Cooke, Vesselina G, Davids, Matthew S, DeAngelo, Daniel J, Dorfman, David M, Eaton, Hilary, Ebert, Benjamin L, Etchin, Julia, Firestone, Brant, Fisher, David C, Freedman, Arnold S, Galinsky, Ilene A, Gao, Hui, Garcia, Jacqueline S, Garnache-Ottou, Francine, Graubert, Timothy A, Gutierrez, Alejandro, Halilovic, Ensar, Harris, Marian H, Herbert, Zachary T, Horwitz, Steven M, Inghirami, Giorgio, Intlekofer, Andrew M, Ito, Moriko, Izraeli, Shai, Jacobsen, Eric D, Jacobson, Caron A, Jeay, Sébastien, Jeremias, Irmela, Kelliher, Michelle A, Koch, Raphael, Konopleva, Marina, Kopp, Nadja, Kornblau, Steven M, Kung, Andrew L, Kupper, Thomas S, LeBoeuf, Nicole R, LaCasce, Ann S, Lees, Emma, Li, Loretta S, Look, A Thomas, Murakami, Masato, Muschen, Markus, Neuberg, Donna, Ng, Samuel Y, Odejide, Oreofe O, Orkin, Stuart H, Paquette, Rachel R, Place, Andrew E, Roderick, Justine E, Ryan, Jeremy A, Sallan, Stephen E, Shoji, Brent, Silverman, Lewis B, Soiffer, Robert J, Steensma, David P, Stegmaier, Kimberly, Stone, Richard M, Tamburini, Jerome, Thorner, Aaron R, van Hummelen, Paul, Wadleigh, Martha, Wiesmann, Marion, Weng, Andrew P, Wuerthner, Jens U, Williams, David A, Wollison, Bruce M, Lane, Andrew A, Letai, Anthony, Bertagnolli, Monica M, Ritz, Jerome, Brown, Myles, Long, Henry, Aster, Jon C, Shipp, Margaret A, Griffin, James D, Weinstock, David M

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Cancer cell, 2016
Townsend, Elizabeth C, Murakami, Mark A, Christodoulou, Alexandra, Christie, Amanda L, Köster, Johannes, DeSouza, Tiffany A, Morgan, Elizabeth A, Kallgren, Scott P, Liu, Huiyun, Wu, Shuo-Chieh, Plana, Olivia, Montero, Joan, Stevenson, Kristen E, Rao, Prakash, Vadhi, Raga, Andreeff, Michael, Armand, Philippe, Ballen, Karen K, Barzaghi-Rinaudo, Patrizia, Cahill, Sarah, Clark, Rachael A, Cooke, Vesselina G, Davids, Matthew S, DeAngelo, Daniel J, Dorfman, David M, Eaton, Hilary, Ebert, Benjamin L, Etchin, Julia, Firestone, Brant, Fisher, David C, Freedman, Arnold S, Galinsky, Ilene A, Gao, Hui, Garcia, Jacqueline S, Garnache-Ottou, Francine, Graubert, Timothy A, Gutierrez, Alejandro, Halilovic, Ensar, Harris, Marian H, Herbert, Zachary T, Horwitz, Steven M, Inghirami, Giorgio, Intlekofer, Andrew M, Ito, Moriko, Izraeli, Shai, Jacobsen, Eric D, Jacobson, Caron A, Jeay, Sébastien, Jeremias, Irmela, Kelliher, Michelle A, Koch, Raphael, Konopleva, Marina, Kopp, Nadja, Kornblau, Steven M, Kung, Andrew L, Kupper, Thomas S, LeBoeuf, Nicole R, LaCasce, Ann S, Lees, Emma, Li, Loretta S, Look, A Thomas, Murakami, Masato, Muschen, Markus, Neuberg, Donna, Ng, Samuel Y, Odejide, Oreofe O, Orkin, Stuart H, Paquette, Rachel R, Place, Andrew E, Roderick, Justine E, Ryan, Jeremy A, Sallan, Stephen E, Shoji, Brent, Silverman, Lewis B, Soiffer, Robert J, Steensma, David P, Stegmaier, Kimberly, Stone, Richard M, Tamburini, Jerome, Thorner, Aaron R, van Hummelen, Paul, Wadleigh, Martha, Wiesmann, Marion, Weng, Andrew P, Wuerthner, Jens U, Williams, David A, Wollison, Bruce M, Lane, Andrew A, Letai, Anthony, Bertagnolli, Monica M, Ritz, Jerome, Brown, Myles, Long, Henry, Aster, Jon C, Shipp, Margaret A, Griffin, James D, Weinstock, David M

Targeting transcription regulation in cancer with a covalent CDK7 inhibitor.

Nature, 2014
Kwiatkowski, Nicholas, Zhang, Tinghu, Rahl, Peter B, Abraham, Brian J, Reddy, Jessica, Ficarro, Scott B, Dastur, Anahita, Amzallag, Arnaud, Ramaswamy, Sridhar, Tesar, Bethany, Jenkins, Catherine E, Hannett, Nancy M, McMillin, Douglas, Sanda, Takaomi, Sim, Taebo, Kim, Nam Doo, Look, Thomas, Mitsiades, Constantine S, Weng, Andrew P, Brown, Jennifer R, Benes, Cyril H, Marto, Jarrod A, Young, Richard A, Gray, Nathanael S

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia.

The Journal of clinical investigation, 2014
Gutierrez, Alejandro, Pan, Li, Groen, Richard W J, Baleydier, Frederic, Kentsis, Alex, Marineau, Jason, Grebliunaite, Ruta, Kozakewich, Elena, Reed, Casie, Pflumio, Francoise, Poglio, Sandrine, Uzan, Benjamin, Clemons, Paul, VerPlank, Lynn, An, Frank, Burbank, Jason, Norton, Stephanie, Tolliday, Nicola, Steen, Hanno, Weng, Andrew P, Yuan, Huipin, Bradner, James E, Mitsiades, Constantine, Look, A Thomas, Aster, Jon C

TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.

Cancer discovery, 2013
Sanda, Takaomi, Tyner, Jeffrey W, Gutierrez, Alejandro, Ngo, Vu N, Glover, Jason, Chang, Bill H, Yost, Arla, Ma, Wenxue, Fleischman, Angela G, Zhou, Wenjun, Yang, Yandan, Kleppe, Maria, Ahn, Yebin, Tatarek, Jessica, Kelliher, Michelle A, Neuberg, Donna S, Levine, Ross L, Moriggl, Richard, Müller, Mathias, Gray, Nathanael S, Jamieson, Catriona H M, Weng, Andrew P, Staudt, Louis M, Druker, Brian J, Look, A Thomas

Comprehensive microRNA expression profiling of the hematopoietic hierarchy.

Proceedings of the National Academy of Sciences of the United States of America, 2010
Petriv, O I, Kuchenbauer, F, Delaney, A D, 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, C J F, Weng, A P, Piret, J, Eaves, C, Marra, M A, Humphries, R K, Hansen, C L

Per-channel basis normalization methods for flow cytometry data.

Cytometry. Part A : the journal of the International Society for Analytical Cytology, 2010
Hahne, Florian, Khodabakhshi, Alireza Hadj, Bashashati, Ali, Wong, Chao-Jen, Gascoyne, Randy D, Weng, Andrew P, Seyfert-Margolis, Vicky, Bourcier, Katarzyna, Asare, Adam, Lumley, Thomas, Gentleman, Robert, Brinkman, Ryan R

Projects

Leukemia stem cells in T-ALL

We are continuing our work examining the roles of PKCθ and Wnt signaling, as well as pursuing exciting new leads emanating from our human cord blood model, in establishing/maintaining leukemia stem cell activity in T-ALL.

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.

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.

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, Nature Communications, 2019). This model generates polyclonal expansions of pre-leukemia cells in vitro within 3-4 weeks, which then produce clonal T-ALL disease within 3 months after injection into immunodeficient mice. Using this model, we are actively exploring the following areas:

Sponsors

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