Dr. Andrew P. Weng, MD, PhD
- Postdoctoral Research Fellow in Pathology (Supervisor: Dr. Jon Aster)
Women’s Hospital/Harvard Medical School
July 2000 – May 2004
- Clinical Fellow in Hematopathology
Brigham & Women’s Hospital/Harvard Medical School
July 1999 – June 2000
- Resident in Anatomic Pathology
Women’s Hospital/Harvard Medical School
July 1997 – June 1999
Professional Experience (Research):
- Senior Scientist, Terry Fox Laboratory,
BC Cancer Agency (BCCA), since Jan 2005
- Associate Professor,
Pathology & Laboratory Medicine, UBC,
since Jul 2011
- Assistant Professor,
Pathology & Laboratory Medicine, UBC, 2004-2011
- Clinician Scientist, Department of Pathology, BCCA, since Jun 2004
- Instructor, Department of Pathology, Harvard Medical School,
Professional Experience (Clinical):
- Director, Hematopathology,
BCCA, since Oct 2006
- Director, Clinical Flow Cytometry Lab, BCCA, since Sep 2005
- Hematopathologist, BCCA,
since Jun 2004
- Hematopathologist, Dana Farber Cancer Institute, 2001-2004
- Associate Pathologist,
Brigham & Women's Hospital, 2001-2004
- Notch Signaling
My research focuses on signal transduction via the Notch receptor in lymphoid cells. Notch signaling plays an important role in directing
lymphoid progenitors towards T cell fate, and when dysregulated leads to transformation of immature T cells and the development of T-cell
acute lymphoblastic leukemia/lymphoma (T-ALL). By modulating Notch signals both in normal lymphoid development and in established human and
mouse T-ALL tumors, we have been investigating molecular events responsible for cell fate determination and oncogenic transformation. Many
of our findings have direct relevance to the development of rational therapies in the treatment of T-ALL.
- Identifying and characterizing leukemia stem cells. Cancer stem cells are defined experimentally as cellular subsets responsible for serial transplantability in animal models and give rise to both CSC and non-CSCs by asymmetric division, and serve as a model for human disease relapse which invariably occurs in the context of prior chemotherapy. Our current studies have identified two distinct genetic pathways which impact on LSC activity in murine models of T-ALL, and continuing efforts will characterize these pathways in human T-ALL xenograft models as well.
- Identifying and characterizing genetic events that collaborate with Notch signaling in leukemogenesis. We are performing retroviral insertional mutagenesis screens on various genetic backgrounds of Notch leukemias such as Pten and Ink4a/Arf null, as well as genetic variants involving our two identified LSC-modulating pathways.
- Characterization of Notch-regulated microRNAs. We have performed microRNA profiling in the context of both murine and human T-ALL cells, and identified a limited number of candidates for which we are characterizing predicted target mRNAs and functional contribution to the leukemia phenotype.
- Modeling of pediatric vs. adult T-ALL. While pediatric disease is largely curable, the same disease in adults leads to 60% mortality. While to some extent this difference could be attributable to more robust physiologic reserves of young patients, we have preliminary data suggesting that T-ALL generated from adult and pediatric programmed progenitors exhibit distinct biological properties which could underlie the phenotypic differences observed in patients.
- We are also just branching out into studies involving cancer stem cells in AML, and also survival pathways in non-Hodgkin lymphoma. The latter project takes advantage of the extensive primary lymphoma tissue bank and corresponding clinical database at the BC Cancer Agency.
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 2013.
(Epub ahead of print).
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 2013 (Epub ahead of print) (Weng AP
is a member of the FlowCAP Consortium).
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 2012 (* equal
contribution) (Epub ahead of print).
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
cover of the Nov 2012 issue)
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
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.
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.
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
119: 1963-1971, 2012.
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.
Dakappagari N, Ho SN, Gascoyne RD, Ranuio J, Weng AP*,
(*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.
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.
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
2011. 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)
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.
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,
AP, Piret J, Eaves C, Marra MA,
RK & Hansen CL. Comprehensive microRNA expression profiling of
the hematopoietic hierarchy. Proc Natl Acad Sci
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.
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.
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,
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.
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.
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.
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,
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):
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.
Weng AP, & Lau A. Notch signaling
in T-cell acute lymphoblastic leukemia. Future Oncol 1 (4): 511-9,
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.
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.
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):
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):
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.
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.
Weng AP, & Aster JC. Multiple
niches for Notch in cancer: context is everything. Curr Opin Genet
Dev 14 (1): 48-54, 2004.
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.
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.
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):
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.
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.
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.
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.
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.
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,
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.
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):
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.
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.
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.
Terry Fox Laboratory
BC Cancer Agency
675 West 10th
Canada V5Z 1L3
Terry Fox Laboratory
BC Cancer Agency
675 West 10th
Canada V5Z 1L3