PhD, University of Toronto
At a Glance
- we focus on understanding the molecular circuitry that controls normal and malignant blood stem cell function.
- a major area of interest is post-transcriptional control mediated by RNA binding proteins and microRNAs.
- we use a combination of in vitro and in vivo models of pre- and frank malignant myeloid neoplasms and work with both mouse stem cells and human stem cells from primary patient samples.
- we employ a multidisciplinary approach that capitalizes on methodologies including lentiviral transductions, xenotransplantations, flow cytometry, CRISPR screening and integrative omics (transcriptomics, CLIP-seq and proteomics).
- we aim to apply our findings to advance the design of novel stem cell-directed regenerative and anti-leukemic therapies.
Kristin Hope is a Senior Scientist at the Princess Margaret Cancer Centre, University Health Network, and Associate Professor in the Dept. of Medical Biophysics at the University of Toronto. Dr. Hope earned a Ph.D. Degree in Molecular Genetics from the University of Toronto. She then went on to a postdoctoral fellowship in Montreal, in the laboratory of Dr. Guy Sauvageau. Dr. Hope started her own laboratory at McMaster University in 2010 and she and her team moved to the University of Toronto in 2020.
Our research sets out to identify novel stem cell regulators that could inform the design of enhanced hematopoietic stem cell-based regenerative therapies one on hand and cancer stem cell-targeted anti-leukemic therapies on the other. In particular we are exploring the premise that RNA binding protein-driven post-transcriptional control is a critical mode by which stemness and transformation are regulated in hematopoiesis. We interrogate this unique paradigm through three major research themes:
Identifying mediators of hematopoietic stem cell self-renewal. Blood stem cell transplants can be a curative cancer treatment however in many cases are limited by donor samples having too few stem cells. Our research uses functional genetics approaches coupled with in vivo pre-clinical stem cell read-outs in xenotransplantation assays to identify post-transcriptional mediators of hematopoietic stem cell expansion.
Defining the RNA binding protein effectors of leukemic stem cell function in myeloid leukemia. Using genetic strategies and loss and gain of function approaches we capitalize on a combination of mouse and primary human leukemia patient sample model systems to identify RNA binding proteins whose dysregulation underlies leukemogenesis and leukemic stem cell-driven relapse.
Dissecting the integrated role of RNA binding proteins in stemness from a systems perspective. RNA binding proteins synchronously regulate the fates of functionally similar RNAs, in what have been termed “RNA regulons”. We use a variety of unbiased genome and proteome scale approaches to define the rules that govern this regulation and determine key downstream circuitries of stem cell regulating RNA binding proteins whose targeting could provide the basis for novel regenerative and/or anti-leukemic treatments.
- Ly M, Rentas S, Vujvoic A, Wong N, Moreira S, Holzapfel N, Bhatia S, Tran D, Minden M,Draper J, Hope KJ. (2019). Diminished aryl hydrocarbon receptor signalling drives human acute myeloid leukemia stem cell maintenance. Cancer Research, Nov 15;79(22):5799-5811.
- Espinoza DA, Fan X, Yang D, Cordes S, Truitt LL, Calvo KR, Yabe IM, Demirci S, Hope KJ, Hong SG, Krouse A, Metzger ME, Bonifacino AC, Lu R, Uchida N, Tisdale J, Wu X, De Ravin SS, Malech H, Donahue RE, Wu C, and Dunbar C (2019). Aberrant Clonal Hematopoiesis Following Lentiviral Transduction of HSPC in a Rhesus Macaque. Molecular Therapy. Jun 5;27(6); 1074-1086.
- De Rooij L, Keyvani Chahi A, Chan D, Hope KJ. (2018) Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control. Biochemistry and Cell Biology. Jun 13: 1-11.
- Belew MB, Bhatia S, Keyvani Chahi A, Rentas S, Draper JS, Hope KJ. (2018). PLAG1 and USF2 regulate hematopoietic stem cell-specific expression of Musashi-2. Stem Cell Reports. (10(4): 1384-1397.
- Rentas S, Holzapfel N, Belew M, Pratt G, Voisin V, Bader G, Wilhelm B, Yeo G, Hope KJ. (2016). Musashi2 Attenuates AHR Signaling to Expand Human Hematopoietic Stem Cells. Nature, 532(7600): 508-11.
- Cellot S, Hope KJ, Sauvageau M, Chagraoui J, Deneault E, MacRae T, Mayotte TN, Wilhelm BT, Landry JR, Ting SB, Krosl J, Thompson A, Humphries K and Sauvageau G. (2013). RNAi screen identifies Jarid1b as a major regulator of mouse HSC self-renewal. Blood. 122(9):1545-55.
- Hereault O*, Hope KJ*, Deneault E, Mayotte N, Chagraoui J, Whilhelm BT, Cellot S, Sauvageau M, Andrade-Navarro MA, and Sauvageau G*. (2012). A role for GPx3 in activity of normal and leukemia stem cells. Journal of Experimental Medicine. 209(5):895-901. *authors made equal contribution.
- Hope KJ, Cellot S, Ting S, MacRae T, Mayotte N, Iscove NN, Sauvageau G. (2010). An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity. Cell Stem Cell. 7(1):101-113.