Biennial Research Report 2005 ‐2006

T ERRY F OX L ABORATORY BCCA CANCER RESEARCH CENTRE

LABORATORY 675 West 10th Avenue, , BC Tel: 604‐675‐8120 FOX

Y

Our Research Focus: TERR The Terry Fox Laboratory (TFL) was created in 1981 as a joint undertaking between the BC Cancer Agency, the BC Cancer Foundation, the University of and the National Cancer Institute of . By the end of 2005, TFL had grown to comprise a group of over 150 researchers, including a vibrant training program involving 42 undergraduate students, 33 graduate students and 27 postdoctoral (MD and PhD) fellows. The TFL also includes a Flow Cytometry Core Facility that services the needs of investigators throughout the BCCA as well as the Stem Cell Service, a specialized provincial clinical support program in hematology and oncology. The Stem Cell Service provides the laboratory support for the Leukemia/Bone Marrow Transplantation Program of BC and also an investigational diagnostic laboratory for hematologists and oncologists throughout BC.

TFL research is focused on obtaining solutions to biological questions and problems that will lead to major advances in the diagnosis and treatment of human cancers. These include the development of a broad spectrum of approaches, new systems and experimental models, and the use of primary human samples as well as cells and animals to elucidate the cellular and molecular perturbations that confer malignant potential on cells and to devise more effective methods for eliminating malignant cells. In 2005‐2006, specific tumour types being investigated included acute and chronic myeloid leukemia and the myelodysplastic disorders, lymphoma and breast cancer.

Progress Highlights during 2005 and 2006 ¾ The discovery that the protein SHIP controls the activity of macrophages so that they do not overreact in response to bacterial and viral attacks. This knowledge is being used to develop new strategies to treat allergies, auto‐immune disorders and to control septic shock in hospital patients. ¾ The discovery of a novel pathway by which natural killer cells with previously unknown properties can develop in both the thymus and lymph nodes. ¾ The discovery of how a large class of natural killer receptor genes important for innate immunity and tumour defense are controlled by epigenetic changes to DNA (DNA methylation and histone modifications). ¾ The discovery that mutations in the telomerase gene are a common cause of bone marrow failure in humans who inherit a predisposition to this disease. ¾ The discovery that more than half of all children with T‐cell acute lymphoblastic leukemia share a mutation in a Notch gene leading to activation of myc. ¾ The discovery of a new gene (TGIF) that modulates the rate of fibroblast cell proliferation.

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¾ The discovery of rapidly dividing stem cells in the normal breast that can individually regenerate an entire mammary gland and have features shared by bad prognosis breast cancer. ¾ The discovery that blood‐forming stem cells undergo an abrupt developmental switch soon

LABORATORY after birth that causes most of them to suddenly stop dividing.

¾ The discovery of a new agent for killing human acute leukemia cells that may be more FOX

Y effective in patients ¾ The discovery of how several different pairs of genes and mutations may collaborate to cause

TERR leukemia.

Key Research Staff Researcher name Position & Cross‐Appointments Allen Eaves MD, PhD Medical Director Biophysics, FRCPC, FACP Professor, Medicine, UBC Professor, Pathology & Laboratory Medicine, UBC Ryan Brinkman PhD Genetics Senior Scientist Assistant Professor, Medical Genetics, UBC Connie Eaves PhD Immunology Director (Starting January 1, 2007) Professor, Medical Genetics, UBC Associate Member, Medicine, UBC Associate Member, Pathology & Laboratory Medicine, UBC Member, Exp Medicine, Exp Pathology, Genetics Program, Oncology Program, UBC Donna Hogge MD, PhD Experimental Senior Scientist Pathology, FRCPC Clinical Professor, Medicine, UBC Sr Hematologist Leukemia/BMT Program of BC Member, Exp Medicine, Genetics Program, Oncology Program, UBC Pamela Hoodless PhD Biochemistry Senior Scientist Assistant Professor, Medical Genetics, UBC Member, Genetics Program, Oncology Program, UBC Keith Humphries MD, PhD Medical Genetics Senior Scientist Professor, Medicine, UBC Associate Member, Medical Genetics, UBC Member, Exp Medicine, Exp Pathology, Genetics Program, Oncology Program, UBC Xiaoyan Jiang MD, PhD Molecular Research Scientist Biology Assistant Professor, Medical Genetics, UBC Professor, Medical Genetics, UBC Member, Genetics Program, UBC Gerald Krystal PhD Biochemistry Senior Scientist Professor, Pathology and Laboratory Medicine, UBC Member, Exp Medicine, Exp Pathology, UBC Member, Genetics Program, Oncology Program, UBC

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Peter Lansdorp MD, PhD Experimental Senior Scientist Hematology Director, Flow Cytometry Core, BCCA Professor, Medicine, UBC Associate Member, Medical Genetics, UBC LABORATORY

Member, Genetics Program, Oncology Program, UBC Dixie Mager PhD Medical Biophysics Senior Scientist FOX

Professor, Medical Genetics, UBC

Member, Genetics Program, Oncology Program, UBC Y Clayton Smith MD, FRCPC Senior Scientist

Clinical Associate Professor, Medicine, UBC TERR Director, Leukemia/Bone Marrow Transplantation Program of BC Fumio Takei PhD Immunology Senior Scientist Professor, Pathology and Laboratory Medicine, UBC Associate Member, Medical Genetics Member, Exp Pathology, Genetics Program, Oncology Program, UBC Andrew Weng MD, PhD Molecular Senior Scientist Genetics and Cell Biology Clinical Scientist, Pathology, BCCA Assistant Professor, Pathology & Laboratory Medicine, UBC Member, Oncology Program, UBC

Training A) Course Instruction R Brinkman UBC MEDG 420 R Kay MEDG 420 R Brinkman UBC MEDG 548C R Kay MEDG 521 C Eaves UBC MEDG 548C G Krystal UBC Path 500A D Hogge UBC Medicine II: Blood & G Krystal MEDG 521 Lymphatics G Krystal MEDG 410 D Hogge UBC Pathology 548R G Krystal PATH 402 P Hoodless UBC MEDG 545 G Krystal UBC Immunology 431: BCCA Med Oncol Residents P Hoodless UBC MEDG 521/ PATH 531 P Lansdorp UBC Med Gen 521 P Hoodless UBC MEDG 515 D Mager UBC MEDG 545 K Humphries UBC Pathology 500 D Mager UBC MEDG 420 K Humphries Stem Cell Directed Studies Seminar D Mager UBC MEDG 530 X Jiang UBC FMED 428 F Takei UBC Oncology 502 R Kay UBC MEDG 545

B) Summary of Trainees Total No. of Post‐doctoral Post‐graduate Undergraduate Clinical Trainees 2005 102 27 33 42 0 2006 100 33 41 26 0

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C) Current Students – Degrees Completed Name Supervisor Date Completed PhD Michelle Bowie C Eaves 2006 Brad Dykstra C Eaves 2006 LABORATORY

Lynn Mar P Hoodless 2006 Rhonna Gurevich K Humphries 2005 FOX Nadine Beaulieu R Kay 2006 Y Iris Cheung P Lansdorp 2005 Louie Van de Lagemaat D Mager 2006

TERR Linnea Veinotte F Takei 2006 MSc Andrea Tegzes C Eaves 2006 Sanja Sekulovic K Humphries 2005 Lisa Dreolini F Takei 2005 Matt McLeod F Takei 2006

D) Trainee Awards Name Supervisor Award Received Michelle Bowie C Eaves CIHR Transplant Partial Studentship (2003‐2006) Christina Chan C Eaves NSERC Industry Graduate Studentship (2006‐2007) Michael Copley C Eaves UBC Graduate Entrance Studentship (2006‐2007) Brad Dykstra C Eaves NCIC TTF Research Studentship (2003‐2008) Peter Eirew C Eaves Stem Cell Network Graduate Studentship (2006) NCIC Graduate Studentship (2006‐2007) CIBC Interdisciplinary Graduate Studentship (2006‐2007) Department of Defense Breast Cancer Program ‐Post Graduate Award (2006‐2009) Clive Glover C Eaves CIHR Doctoral Research Award (2004‐2007) Melanie Kardel C Eaves NSERC Graduate Fellowship (2004‐2005) CIHR Canada Graduate Studentship (2005‐2008) MSFHR Studentship (2005) Sean Kennedy C Eaves NSERC Studentship (2003‐2005) David Kent C Eaves Stem Cell Network Graduate Studentship (2004‐2006) UBC/MSFHR/CIHR Transplant Partial Studentship (2005‐ 2007) CIHR Doctoral Research Award (2006‐2009) Min Lu C Eaves Industrial NSERC Postdoctoral Fellowship (2006‐2007) Kai Lucke C Eaves German Government Postdoctoral Fellowship (2004‐2006) Michael O’Connor C Eaves CIHR Industry‐Partnered Postdoctoral Fellowship (2006‐2009) Afshin Raouf C Eaves CIHR Postdoctoral Fellowship (2004‐2007) Andrea Tegzes C Eaves NSERC Industrial Studentship (2004‐2006) Yun Zhao C Eaves Leukemia Research Fund Postdoctoral Fellowship (2004‐2007) Andrew Muranyi D Hogge UBC Graduate Studentship (2004‐2005) Robin Dickinson P Hoodless MSFHR Postdoctoral Fellowship (2005) Ali Saleem Hassan P Hoodless UBC Graduate Entrance Studentship (2006‐2007) Sam Lee P Hoodless UBC Graduate Entrance Studentship (2006‐2007) Kristen McKnight P Hoodless NSERC Studentship (2004‐2007) Pavie Vrljicak P Hoodless UBC Graduate Entrance Studentship (2004‐2006) Bob Argiropoulos K Humphries Leukemia Research Fund Postdoctoral Fellowship (2006‐2008)

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Michael Heuser K Humphries Deutsche Forschungsgemeinschaft Fellowship (2005‐2007) Koichi Hirose K Humphries MSFHR Postdoctoral Fellowship (2003‐2005) Florian Kuchenbauer K Humphries Deutsche Forschungsgemeinschaft Fellowship (2005‐2007) Eric Yung K Humphries MSFHR Fellowship (2005) CIHR Fellowship (2005 ‐ 2008) LABORATORY

Frann Antignano G Krystal NSERC Studentship (2003 ‐ 2006) MSFHR Junior Graduate Studentship (2004‐2006) FOX

Melisa Hamilton G Krystal MSFHR Studentship (2006 2008) CIHR Canada Graduate Scholarship – Master’s Award Y (20062007)

Victor Ho G Krystal NSERC Studentship (2006 ‐ 2007) TERR Michael Rauh G Krystal/ AW CIHR MD/PhD Studentship (2000 ‐ 2007) Chow Iris Cheung P Lansdorp CIHR Canada Graduate Studentship (2003‐2005) Michelle Decker P Lansdorp MSFHR Studentship (2006‐2007) Matthew Greenwood P Lansdorp Stem Cell Network Graduate Studentship (2003‐2005) Irina Maksakova D Mager Roman Babicki Studentship (2005‐2006) UBC Graduate Studentship (2006‐2007) Dafni Reiss D Mager Multiple Sclerosis Society of Canada Fellowship (2006‐2008) Mark Romanish D Mager Harry and Florence Dennison Fellowship in Medical Research (2006‐2007) Edward Squires Memorial Scholarship (2004‐2005) Arefeh Rouhi D Mager NSERC Studentship (2003‐2005) MSFHR Studentship (2006) Louie Van De D Mager CIHR Doctoral Research Award (2004‐2006) Lagemaat Valeria Alcon F Takei Leukemia Research Postdoctoral Fellowship (2006‐2008) Eva Backstrom F Takei Swedish Research Council & Leukemia Research Fund Postdoctoral Fellowships (2005‐2008) Lisa Dreolini F Takei NSERC Studentship (2003 – 2005) Motoi Maeda F Takei Leukemia Research Foundation (2003‐2005) Linnea Veinotte F Takei MSFHR Studentship (2004‐2005)

Current Awards and Honours Name Distinguished Award/Honour C Eaves Terry Fox Medal of the BC Medical Society (2005) Till and McCulloch Lecturer of the Stem Cell Network (2006) R Brinkman ISAC Scholar, International Society for Analytical Cytometry (2006) P Hoodless CIHR New Investigator Scholar Award (2003‐2008) X Jiang MSFHR Scholar Award (2005) C Smith MSFHR Scholar Award (2003‐2008) A Weng Benjamin Castleman Award, U. S. & Canadian Academy of Pathology (2005) United Food & Commercial Workers Union Award (Highest rated operating grant for 2006 funding cycle, Leukemia & Lymphoma Society of Canada) MSFHR Scholar Award (2005)

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Select Current Contributions Name Membership/Committee Involvement Allen Eaves Director, Stem Cell Service Chair, MITACS Board of Directors

LABORATORY Member, Board of Directors of the Stem Cell Network

Ryan Brinkman Member, Int’l Society for Analytical Cytometry Data Standards Task Force FOX

Member, MSFHR Junior Graduate Scholarship Review Committee

Y Connie Eaves Chairman & Supervisor, Management Committee of Joint Animal Facility, BCCA Chair, NCIC Hematopoiesis & Growth Factors Review Panel

TERR Associate Scientific Director, Stem Cell Network of Canada Member, Board of Genome Canada Member, 2005 Amer Assoc for Cancer Research Program Committee Member Int Society of Experimental Hematology Awards Committee Donna Hogge Director, Cryogenic Laboratory, Stem Cell Service Pamela Hoodless Chair, MSFHR Senior Graduate Trainee Awards Committee Chair, MSFHR Post Doctoral Fellowship Trainee Awards Committee Alberta Cancer Board Research Initiative Program Grant Competition Keith Humphries Chair, Canadian Council of American Society for Gene Therapy Director, Transgenic and Gene Targeting Facility, BCCA Associate Editor, Experimental Hematology Member, Leukemia Research Fund of Canada Scientific Review Panel Member, External Advisory Board Center (to establish a Center for non‐embryonic human stem cells) for Stem Cell and Regenerative Medicine, Case Western University, Cleveland, OH Member, CIHR Developmental Biology Grants Committee Member, Steering Committee of the Canada‐California Strategic Innovation Partnership on Cancer Stem Cells Elected Vice‐President, President‐Elect and President, International Society for Experimental Hematology Xiaoyan Jiang Panel Member, MSFHR Biomedical Postdoc Fellowship Review Committee NIH‐NHLBI Peer Review Panel Member, Special Emphasis Panel for Myelodysplastic Syndrome (RFA HL‐04‐033) and Myeloproliferative Disorders (RFA HL‐04‐034) Columbia, MD Robert Kay Member, Medical Genetics Graduate Program Advisory Committee Member, Genetics Graduate Program Advisory Committee Gerald Krystal Member, Pathology & Laboratory Medicine Promotions Committee, UBC Peter Lansdorp Member, UBC Faculty of Medicine Nominating Committee Member, CIHR Genetics Review Panel Member, Board of Directors, National Cancer Institute of Canada Member, American Society of Hematology Scientific Committee on Stem Cells Advisory Board Member, International Society of Stem Cell Research Special Emphasis Panel, NHLBI, Washington DC Dixie Mager Member, Radiation Safety Committee, BCCA Member, MEDG Teaching Award Committee Member, Planning Committee for Genetics Graduate Program, UBC Member, MSFHR Studentship Review Committee Member, CIHR Genetics Review Panel Clayton Smith Member, BC Cancer Agency Tumour Site Leadership Council Member, International Society of Cellular Therapy Advisory Board Fumio Takei Member, NCIC Immunology Grants Panel

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Current Research Projects3

1. Activation and proliferation of purified hemopoietic stem cells PI: P Lansdorp This project examines the role of telomerase and telomeres in NIH controlling blood cell production throughout life. This project LABORATORY $187,500 (2005) will test the hypothesis that the replication history of $187,500 (2006) hematopoietic stem cells is traceable by examining telomere FOX $595,758 (2002‐2007) length. Y 2. A phase I study of DT388IL3 fusion protein in patients with relapsed and refractory acute myeloid

leukemia TERR PI: D Hogge The goal of this study is to assess dosage and toxicity of a Leukemia Research Fund of Canada sterilized recombinant diphtheria fusion protein – DT388IL3 – in $43,500 (2005) a clinical trial of patients with acute myeloid leukemia. $43,500 (2006) $87,000 (2004‐2006)

3. A novel transplant protocol for chronic myelogenous leukemia PI: A Eaves, C Eaves, M de Lima This project will evaluate three purging methods to selectively (MD Anderson) eliminate chronic myelogenous leukemia stem cells ex vivo. NIH $67,500 (2005) $132,500 (2004‐2006) 4. A quantitative and comprehensive atlas of gene expression in mouse development ‐ Genome Canada Competition II award Co‐PI: M Marra, P Hoodless For project description see Genome Sciences Centre Genome Canada 5. Bioinformatic standards for flow cytometry PI: R Brinkman This project is a multidisciplinary collaboration focused on Co‐PI: C Smith developing data exchange standards for flow cytometry. The NIH scope of this project includes development of an ontology, a data $220,000 (2005) base schema, statistical and visual analysis tools, and a gating $220,000 (2006) standard in the Extensible Markup Language (XML). $1,100,000 (2005‐2010) 6. Biology of cancer: Follicular lymphoma as a model of cancer progression PI: J Connors For project description see Pathology and Laboratory Medicine. Co‐I: A Weng NCIC PPG 7. Cancer Genomics – Genome Canada Competition I award Co‐PI: V Ling, M Marra, C Eaves For project description see Cancer Genetics & Developmental Co‐I: K Humphries, P Lansdorp, et Biology. al. Genome Canada/ Province of BC

3 Key to abbreviations: PI = Principal Investigator, Co‐I = Co‐investigator; CIHR* = Funding Institution; $150,000 (2005‐ 2007) = Total Project Funding for Given Years (*see pages 16‐17 for a list of acronyms)

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8. Cell therapy for muscular disease PI: F Rossi (UBC) The goal is to promote generation of hematopoietic stem cells Co‐PI: K Humphries from murine embryonic stem cells. Stem Cell Network Total to KH ‐ $96,000 (2005‐2008) LABORATORY

9. Characterization of anti‐tumour activity of STEP‐1 FOX PI: C Luer This project will characterize the activity of an apoptosis inducing Y Co‐PI: C Smith factor found in a natural extract using high throughput flow NIH cytometric screening.

TERR Total to CS ‐ $11,700 (2005‐2007) 10. CIHR team grant in cell expansion PI: G Sauvageau (UMontreal) The major goals are: 1) To gain a better understanding of how Co‐I: K Humphries, C Eaves Hox‐related genes regulate hematopoietic stem cell self‐renewal CIHR team grant and 2) to use this information to evaluate the potential of $198,233 (2006) manipulating Hox levels in patients’ stem cells to expand their $1,000,000 (2006‐2011) numbers and improve transplantation‐based therapies where stem cell numbers are limiting.

11. Dependence of human embryonic stem cell self‐renewal on culture variables PI: C Eaves The goal is to study how varying the environment under which Stem Cell Network cells are grown will change the expression of different genes to $34,958 (2005) better control stem cell growth and differentiation. $323,600 (2003‐2005) 12. Development of technologies for the derivation, propagation and differentiation of human embryonic stem cells (HESC) PI: J. Piret (UBC), C Eaves, M This project will lay the groundwork for developing human Bhatia, A Nagy embryonic stem cell‐based therapies and facilitate the broader use Co‐I:, K Humphries, P Lansdorp, A of these cells to identify new drugs that stimulate or repress Karsan, M Marra, et al particular regenerative events in vivo. Stem Cell Network $157,557 (2005) $157,557 (2006) 13. Diagnosis of graft versus host disease using high throughput flow cytometery PI: C Smith The goal is to analyze a previously collected data set comprised of BC Transplant Foundation high throughput flow data obtained from peripheral blood $30,000 (2006) samples at progressive time points following allogeneic $90,000 (2006‐2008) transplantation to identify flow cytometric signatures of GvHD.

14. Disease mechanisms in chronic myeloid lymphoma (CML) PI: A Eaves The goal is to study CML stem cells, since controlling or destroying Co‐PIs: C Eaves, X Jiang these cells is necessary if CML is to be cured. We will look at how NCIC the speed of CML cell multiplication is controlled; what are the $150,000 (2005) properties of these cells that cause leukemia to relapse; and $150,000 (2006) whether a mouse xenografting model can be used to predict the $705,000 (2003‐2011) utility of new drugs for this disease.

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15. Dissecting gene expression networks in mammalian organogenesis Co‐PIs: P Hoodless, M Marra The goal is to focus on the development of three organs in the Co‐I: A Karsan, C Helgason, S mouse embryo, the heart, pancreas, and the liver. In particular, the Jones, S Katz (UBC), E Levy focus is on the tissues in the heart involved in valve formation and (UBC) separation of the chambers, in the pancreas on the formation of LABORATORY Genome Canada Comp. III /Genome islet cells, and in the liver on hepatocytes. BC FOX $224,543 (2006) Y $4,787,197 (2006‐2008) 16. Downstream targets of Notch in lymphoid neoplasia TERR PI: A Weng The goals are to 1) characterize c‐Myc as a Notch target gene and to LLSC 2) identify and characterize additional Notch target genes in a $52,500 (2006) panel of established human tumour cell lines. $105,000 (2006‐2008) 17. Downstream targets of Notch signaling in lymphoid neoplasia PI: A Weng The major goals are 1) to characterize c‐Myc as a Notch target gene LLSC and 2) to identify and characterize additional target genes in a $60,000 (2006) panel of established human tumour cell lines. $180,000 (2006‐2008) 18. Effects of retroelements on mammalian genes PI: D Mager The goal is to understand how mobile genetic elements (“jumping CIHR DNA”) in human and mouse genomes affect the expression and $142,969 (2005) rearrangement of genes. This project will also examine the role that $142,969 (2006) mobile elements may play in determining the qualities that $719,930 (2004‐2009) distinguish humans from our closest relative, the chimpanzee.

19. Gene therapy for sickle cell anemia and β‐thalassemia (Gene transfer and stem cell biology in sickle cell disease and supplement) Co‐PI: C Eaves, K Humphries The goal is successful preclinical development of a gene therapy NHLBI/ NIH protocol for treating patients with sickle cell disease (SCD). US$437,272 (2005) US$62,290 (2006) $2,186,360 (2000‐2005) 20. HOXB4 is an activator of HSC self‐renewal PI: K Humphries, G Sauvageau (U The goals are to 1) enhance the potential of HSCs to expand in Montreal) vitro, 2) develop and test clinically‐relevant strategies aimed at NIH achieving a maximal expansion of HSCs in vitro, 3) identify a $122,962 (2005) HOXB4‐containing “HSC‐renewal protein complex” and 4) $122,962 (2006) determine the role of the newly identified proteins in HSC self‐ $416,000 (2005‐2009) renewal.

21. HOXB4 target‐genes specifying hematopoietic stem cell renewal PI: K Humphries This project will determine the target genes of specific transcription Stem Cell Network factor is in rare cell types with the goal of identifying key transcript $74,899 (2005) subsets that correlate with enhanced HSC self‐renewal capacity. $396,846 (2003‐2005)

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22. Integrated linked kinase as a therapeutic target in acute myeloid leukemia PIs: D Hogge We will test the possibility that abnormal activation of an LLSC intracellular signaling molecule, integrin linked kinase or ILK, is $50,000 (2005) critical to the survival of AML cells including those malignant $50,000 (2006) ‘stem cells’ that allow long‐term growth leukemia in mice and that LABORATORY $150,000 (2006‐2008) inhibition of ILK will result in the death of AML cells while sparing most normal cells. FOX

Y 23. Investigation of the roles of new genes selectively expressed in primitive human mammary epithelial cells

TERR PI: C Eaves The goals are to compare the expression of certain genes in CBCF BC/ Chapter primitive normal human mammary cells their mature progeny, to $50,000 (2006) follow these changes during the differentiation of the primitive $150,000 (2006‐2008) cells in cultures and to test how they may regulate this process.

24. Manipulation of proliferative abnormalities in acute myeloid leukemia (AML) stem cells PI: D Hogge The goal is to characterize the molecular basis of proliferative Cancer Research Society abnormalities in AML cells in order to facilitate the identification $57,000 (2005) of targets for novel therapeutic agents. $114,000 (2003‐2005) 25. Modeling transcriptional networks during cardiac cushion development PI: A Karsan The overarching objective of this program is to elucidate the Co‐PI: P Hoodless transcriptional program of this critical region of the heart (the CIHR endocardial cushions) in human tissues, and generate and $10,000 (2005) to PH. validate a detailed model of this developmental process. $2,391,13 (2005‐2010) 26. Molecular characterization of AHI‐1, a novel signaling molecule with a SH3 and multiple WD40‐ repeat domains, in normal and leukemic hematopoiesis PI: X Jiang The goal is to characterize the functions of Ahi‐1 in regulating MSFHR Estab. Grant normal hematopoietic stem cell proliferation and differentiation $75,000 (2005) using a conditional knockout model system, and to identify and $75,000 (2006) characterize molecular partners involved in normal and altered $225,000 (2005‐2007) signaling pathways regulated by Ahi‐1 using a new proteomics approach (IP+MS).

27. Molecular biology of the initiation of T‐cell transformation by RasGRP1 and Ras GTPases PI: R Kay This project will use a murine model to investigate mechanistic Cancer Research Society links between normal and malignant development of T‐cells and to $60,000 (2005) identify activating mutations in Ras GTPases that frequently occur $60,000 (2006) in T‐cell acute lymphoblastic leukemia $240,000 (2004‐2008)

28. NK and NKT in Herpes simplex virus Type 1 (HSV 1) infection in mice PI: L Kastrukoff (UBC) Resistance to Herpes simplex virus (HSV) infection, which causes Co‐PI: F Takei multiple sclerosis‐like syndrome in mice, is regulated by a gene CIHR cluster encoding multiple receptors on natural killer (NK) cells. $78,720 (2005) The goal of this project is to determine the role of NK cells in $78,720 (2006) immune response to Herpes simplex virus and to identify the $393,600 (2005‐2008) genes and the receptors responsible for the resistance to HSV infection.

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29. NK cell differentiation PI: F Takei The goal of this study is to compare the generation of NK cells CIHR from primitive blood‐forming cells in newborn and adult mice to $128,027 (2005) determine why this process takes a long time. $128,027 (2006) $320,068 LABORATORY (2003‐2007) 30. Normal and leukemic hematopoiesis FOX

PI: K Humphries The overall goal of this program is to determine how normal blood Y Co‐Is: C Eaves, P Hoodless, G cells become leukemia cells and to apply that information to

Krystal, P Lansdorp develop new leukemia treatments. TERR NCIC Group Grant This program is comprised of the following sub‐projects: $5,238,379 (2002‐2007)

Characterization and self‐renewal control of normal hematopoietic stem cells PI: C Eaves $191,400 (2005) $191,400 (2006) The long‐term goal of this project is to develop methods for controlling and manipulating normal hematopoietic stem cell (HSC) expansion. Genetic determinants of hematopoietic stem cell function PI: K Humphries $171,535 (2005) $171,535 (2006) The major goals of this project are to discover and elucidate the roles/mechanisms of novel Hox and related molecules in normal and leukemic hemopoiesis. Regulation of proliferation vs differentiation during normal and leukemic hemopoiesis. PI: G Krystal $127,045 (2005) $126,166 (2006) The major goals of this project are to understand the effects of the TFGβ and PI3K pathways on normal and abnormal hemopoietic cells. Telomere length regulation in murine cells PI: P Lansdorp $173,585 (2005) $175,610 (2006) The goal of this project is to understand telomere length regulation in the mouse and clarify the relation between telomere length and telomere function. TGFβ signal transduction pathways in developmental programs PI: P Hoodless $149,250 (2005) $149,250 (2006) This project examined the role of the transcriptional repressor, TGIF, in embryogenesis, cell cycle and signaling in the mouse.

31. Notch signaling in lymphoid neoplasia PI: A Weng The major goals are to characterize Notch target genes in MSFHR Estab. Grant & Career established human tumour cell lines, and to score these target Dev. Award genes for leukemogenic potential in animal models; also, to $62,500 (2006) characterize promoter elements upstream of candidate Notch $377,500 (2006‐2011) target genes. 32. Notch signaling in lymphoid neoplasia PI: A Weng For project description see Pathology and Laboratory Medicine. NCI Career Development Award

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33. Novel agents for hematopoietic stem cell expansion PI: K Humphries The proposed work will investigate the effectiveness of novel stem CIHR POP cell expanding reagents and to develop them into reagents that can $136,018 (2005) be safely and efficiently used clinically. $136,018 (2005‐2005) LABORATORY

34. Optimization of the use of diphtheria toxin‐growth factor fusion proteins for the treatment of acute leukemia FOX

Y PI: D Hogge The goal is to measure the level of expression of the target CIHR receptors on different leukemia samples and the proliferative

TERR $22,918 (2005) activity the leukemia cells from these samples to determine if these $22,918 (2006) features predict response to the DT‐GF molecules. We will also $68,754 (2004‐2006) determine if combining the DT‐GF molecule with another drug which targets leukemia cells will be more effective than either drug alone.

35. Optimization of the use of diphtheria toxin‐growth factor fusion proteins for the treatment of acute leukemia PI: D Hogge This project is investigating a different class of targeting molecules NCIC in which the diphtheria toxin (DT) is fused to a growth factor (GF) $116,179 (2005) molecule to target leukemic cells. The proposed studies will $116,179 (2006) facilitate the entry of new and improved molecules and patient $350,000 (2005‐2008) selection strategies into clinical trials which may ultimately improve anti‐leukemic therapy for patients with Acute Myeloid Leukemia.

36. Receptors on NK and NKT cells PI: F Takei This goal is to study NKT cells in more detail. In particular, we will NCIC find out what role NKT cells have in the immune system, whether $145,368 (2005) they use the same receptors as NK cells to recognize healthy cells, $145,368 (2006) and what factors stimulate their activity. $735,438(2003‐2008)

37. Regulation of natural killer cell receptor genes PI: D Mager The goal is to elucidate the mechanisms that generate functional CIHR diversity of NK cells – the white blood cells considered to be the $127,700 (2005) first line of immune defense against virus‐infected and cancer cells. $127,700 (2006) The focus is on the receptors on NK cells that recognize MHC $638,500 (2004‐2009) class‐I molecules, and to employ the development of new ways to harness the body’s immune system to eliminate cancer cells.

38. Replicative shortening of telomeres in human cells PI: P Lansdorp The goal is to investigate the role of the human RTEL (regulator of CIHR telomere length) protein in the growth of normal and malignant $132,069 (2005) cells. The objective of this study is to understand the role of $132,069 (2006) telomeres in aging and cancer by addressing specific questions $660,345 (2005‐2010) about the molecular mechanisms of telomere loss.

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39. Role of DNA methylation in controlling syncytin: a novel gene implicated in multiple sclerosis PI: D Mager This project will investigate if the ERV transcriptional promoter of Multiple Sclerosis Society the syncytin gene is a sensitive target for epigenetic regulation and $35,000 (2005) that perturbations in this regulation may be involved in multiple $35,000 (2006) sclerosis. LABORATORY $70,000 (2005‐2006) 40. Role of LFA‐1 in cell mediated cytotoxicity FOX

PI: F Takei The goal of this study is to understand how a protein called LFA‐1 Y CIHR involved in cell‐cell binding acts to initiate the cascade of events to

$58,632 (2005) guide ‘killer lymphoctye’ cells of the immune system to attack TERR $58,632 (2006) diseased cells. $586,315 (2005‐2010) 41. Role of RasGRP1 in BCR‐induced deletion of immature B cells PI: R Kay The goal is to understand the molecular mechanism by which Ras CIHR GRP1 increases the sensitivity of immature B cells to survival $117,336 (2005) signal suppression and induction of cell death. Insight into $117,336 (2006) regulation of B cell activation vs. deletion is critical to ensure $821,347 (2004‐2008) effective immune response to foreign antigens while avoiding auto‐immunity.

42. Role of retroelements in age related gene expression PI: D Mager This project will investigate whether the gradual, age‐related CIHR (Pilot Project) demethylation of retroelements, located within or near genes can $49,942 (2005) lead to altered expression of genes. $49,942 (2006) $100,000 (2006‐2007) 43. Stem cell and gene regulation PI: A Eaves This goal is to enhance studies to understand the molecular Co‐PIs: C Eaves, D Hogge, P pathways that govern stem cell renewal, viability, their Hoodless, K Humphries, R development into specific types of cells, their ability to multiply Kay, G Krystal, P Lansdorp, D and their genome stability. Mager, C Smith, H Sutherland, F Takei MSFHR Research Unit $250,000 (2005) $250,000 (2006) $1,000,000 (2003‐2008) 44. Stem cell centre PI: P Lansdorp This project will address new questions in stem cell biology and CFI explore emerging possibilities for the use of stem cells in $1,008,384 (2005) regenerative medicine. The centre will comprise of three $1,008,384 (2006) laboratories: a stem cell sorting and analysis laboratory, a gene $3,775,195 (2002‐2005) vector laboratory and a Good Manufacturing Practice (GMP) Stem Cell Processing Laboratory.

45. Stem cell centre ‐ infrastructure operating funds PI: P Lansdorp Partial infrastructure operating funds for the stem cell centre CFI project. $110,079 / yr (2005, 2006) $231,346 (2003‐2006)

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46. Stem cells for the treatment of bone marrow failure PI: P Lansdorp The goals are to delineate the frequency and nature of mutations in Co‐I: K Humphries, C Eaves genes encoding telomerase components in patients with various CIHR team grant immunological and hematological disorders and to develop novel $490,225 (2005) therapeutic options for patients. LABORATORY $490,225 (2006) $2,451,125 (2005‐2010) FOX

Y 47. The role of Ahi‐1 in human leukemogenesis PI: X Jiang The aim is to gain new insights into the pathogenesis of human

TERR Leukemia Research Fund leukemia that will ultimately lead to the development of a new $50,000 (2005) rationally designed, molecularly targeted therapies by delineating $50,000 (2006) the normal functions and transforming properties of a new $200,000 (2004‐2008) candidate oncogene (Ahi‐1).

48. The role of novel oncogene (Ahi‐1) in the development of leukemia Pi: X Jiang The goal is to understand the molecular mechanisms of aberrant Cancer Research Society gene regulation and function that contribute to the development of $60,000 (2005) human leukemia ultimately, leading to the development of more $60,000 (2006) effective, molecularly targeted therapies. $240,000 (2003‐2007) 49. The role of SHIP in hemopoiesis and innate immunity PI: G Krystal This project will investigate how the SHIP protein regulates the NCIC activity of different blood cells and their precursors. $150,000 (2006) $750,000 (2005‐2010)

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