The overall goal of my research program is to understand the molecular mechanisms and cellular functions of specific oncogenes, tumor suppressor genes, miRNAs and their target genes in the regulation of the properties of cancer/leukemic stem cells, signal transduction events, initiation and progression of human leukemia and drug resistance. The ultimate objective is to identify molecules and pathways that will lead to new, rationally designed, more effective, and less toxic, personalized molecularly targeted therapies. In particular, we are extremely interested in developing mechanism-based combination therapeutic strategies that can directly target drug-insensitive leukemic stem cells.
My research objectives are currently focused on two lines of investigation. One is basic investigation of the molecular mechanisms of several newly identified cancer driver genes as potential therapeutic targets that contribute to the pathogenesis and drug resistance of a number of human leukemias and lymphomas. By analyzing perturbations in primary human leukemic cells, including patient’s leukemic stem/progenitor cells, by global gene expression profiling, in overexpression and knockdown in vitro and in vivo mouse and patient-derived xenograft models, my research group has recently demonstrated that AHI-1 (Abelson helper integration site-1), a scaffold oncoprotein, is highly deregulated in BCR-ABL+ leukemic stem cells and interacts with multiple kinases and other proteins (BCR-ABL, JAK2, β-catenin, DNM2 and γ-Tubulin, etc) to enhance leukemia-initiating activity and drug-resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). We have also been exploring new, complementary therapeutic strategies that can synergistically target key molecular events active in leukemic stem cells and their associated bone marrow niche, autophagy and the Hedgehog signaling pathway, etc, and have uncovered ILK, ATG4B and several miRNAs/target genes as potential biomarkers and therapeutic targets in CML stem/progenitor cells. Understanding dynamic changes in molecular and signaling events regulated by these critical drivers/networks essential for leukemic stem cell functionality/drug resistance will lead to the development of more effective molecularly targeted therapies, critical especially for patients at high risk of drug resistance and disease progression.
The second line of investigation is a translational research effort in human leukemia, which aims to develop new predictive and prognostic tests and improved treatments for human leukemia, in collaboration with local and global clinical leaders, experts in medicinal chemistry and drug design and large drug companies. We have recently identified several unique features of CML stem/progenitor cells and miRNA/target genes that lead to their intrinsic resistance to TKI therapies and might be expected to predict the responsiveness of patients to TKI therapy. These predictive tests will rapidly identify patients who will not benefit from standard TKI monotherapies so that they may be considered rapidly for transplant-based or novel combination treatments to significantly improve outcomes. We have also been testing new therapeutic agents/inhibitors and combination treatment strategies that can effectively eradicate human leukemic stem cells, using our well-established in vitro and in vivo models
Gul-Uludag H, Valencia-Serna J, Kucharski C, Marquez-Curtis L, Jiang X, Larratt L, Janowska-Wieczorek A and Uludag H. Polymeric nanoparticle-mediated silencing of CD44 receptor in CD34+ acute myeloid leukemia cells. Leukemia Research 38, 1299-1308, 2014.
Lin H, Chen M, Rothe K, Lorenzi MV, Woolfson A, Jiang X. Selective JAK2/ABL dual inhibition therapy effectively eliminates TKI-insensitive CML stem/progenitor cells. Oncotarget 2014 5, 8637-8650, 2014.
Sahin B, Fife J, Parmar MB, Valencia-Serna J, Gul-Uludağ H, Jiang X, Weinfeld M, Lavasanifar A, Uludağ H. siRNA therapy in cutaneous T-cell lymphoma cells using polymeric carriers. Biomaterials 35, 9382-94, 2014.
Huang Y, Litvinov IV, Wang Y, Su MW, Tu P, Jiang X, Kupper TS, Dutz JP, Sasseville D, Zhou Y. Thymocyte selection-associated high mobility group box gene (TOX) is aberrantly over-expressed in mycosis fungoides and correlates with poor prognosis. Oncotarget, 5:4418-25, 2014.
Jiang X. Distinguishing CML LSCs from HSCs using CD26. Blood 123(25):3851-2, 2014.
Rothe K, Lin H , Lin K, Leung A, Wang HM, Malekesmaeili M, Brinkman RR, Forrest DL, Gorski S,Jiang X. The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells. Blood 123: 3622-34, 2014.
Sloma I, Beer PA, Saw KM, Chan M, Leung D, Raghuram K, Brimacombe C, Johnston B, Lambie K, Forrest DL, Jiang X and Eaves CJ. Genotypic and functional diversity of phenotypically defined primitive hematopoietic cells in patients with chronic myeloid leukemia. Exp Hematol 41: 837-47, 2013.
Valencia-Serna J, Gul-Uludag H, Mahdipoor P, Jiang X and Uludag H. Investigating siRNA delivery to chronic myeloid leukemia K562 cells with lipophilic polymers for therapeutic BCR-ABL down-regulation. J Controlled Release 172: 495-503, 2013.
Jardon MA, Rothe K, Bortnik S, Vezenkov L, Jiang X, Young RN, Lum JJ, Gorski SM. Autophagy: From structure to metabolism to therapeutic regulation. Autophagy 12: 2180-2182, 2013.
Chen M, Gallipoli P, DeGeer D, Sloma I, Forrest DL, Chan M, Lai D, Jorgenson H, Ringrose A, Wang HM, Lambie K, Nakamoto H, Saw KM, Turhan A, Arlinghaus R, Barnett MJ, Eaves A, Eaves C, Holyoake TL and Jiang X. Targeting primitive chronic myeloid leukemia cells by effective inhibition of a new AHI-1-BCR-ABL-JAK2 complex. J Natl Cancer Inst 105: 405-423, 2013.
Zeng F, Huang SZ, Chen MJ, Gong ZJ, Baldwin D, Qian H, Yan JB, Wang J, Chen X, Xiao YP, Chalandon Y, Ringrose A, Ren ZR, Eaves A, Eaves C & Jiang X. Long-term deregulated human hematopoiesis in goats transplanted in utero with BCR-ABL-transduced Lin-CD34+ cord blood cells. Cell Research 23: 859-862, 2013.
Valencia-Serna J, Gul-Uludag H, Tang T, Jiang X and Uludag H. Investigating siRNA delivery to chronic myeloid leukemia K562 cells with lipophilic polymers for therapeutic BCR-ABL down-regulation. J Controlled Release 10: 495-503, 2013.
Sloma I, Beer PA, Saw KM, Chan M, Leung D, Raghuram K, Brimacombe C, Johnston B, Lambie K, Forrest DL, Jiang X and Eaves CJ. Genotypic and functional diversity of phenotypically defined primitive hematopoietic cells in patients with chronic myeloid leukemia. Exp Hematology 41: 837-847, 2013.
Jardon MA, Rothe K, Bortnik S, Vezenkov L, Jiang X, Young RN, Lum JJ, Gorski SM. Autophagy: From structure to metabolism to therapeutic regulation. Autophagy 12: 1-3, 2013.
Landry B, Aliabadi HM, Samuel A, Gul H, Jiang X, Kutsvh O, Uludag H. Effective non-viral delivery of siRNA to acute myeloid leukemia cells with lipid-substituted polyethylenimines PLoS One 7, e44997, 2012.
Liu X, Chen M, Lobo P, An J, Cheng SWG, Moradian A, Morin GB, Van Petegem F and Jiang X. Molecular and structural characterization of the SH3 domain of AHI-1 in regulation of cellular resistance of BCR-ABL+ chronic myeloid leukemia cells to tyrosine kinase inhibitors. Proteomics 12: 2094-2106, 2012.
Esmailzadeh S, Jiang X. AHI-1: a novel signaling protein and potential therapeutic target in human leukemia and brain disorders. Oncotarget 12: 918-934, 2011.
Wang Y, Su M, Zhou LL, Tu P, Zhang X, Jiang X, Zhou Y. Deficiency of SATB1 expression in Sezary cells causes apoptosis resistance by regulating FasL/CD95L transcription. Blood 117:3826-35, 2011.
Sloma I, Jiang X, Eaves AC, Eaves CJ. Insights into the stem cells of chronic myeloid leukemia. Leukemia 24:1823-1833, 2010.
Grant H, Jiang X, Stebbing J, Foroni L, Craddock C, Griffiths M, Clark RE, O’Brien S, Khorashad JS, Gerrard G, Wang L, Irving JAE, Wang M, Karran L, Dyer MJS, Forrest D, Page K, Eaves CJ, Woolfson A. Analysis of BCR-ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype. Leukemia 10: 1817-1821, 2010.
Jiang X (Corresponding author), Forrest D, Nicolini F, Turhan A, Guilhot J, Yip C, Holyoake T, Jorgensen H, Lambie K, Saw KM, Pang E, Vukovic R, Lehn P, Ringrose A, Yu M, Brinkman RR, Smith C, Eaves A and Eaves C. Properties of CD34+ CML stem/progenitor cells that correlate with clinical response to imatinib mesylate. Blood 116: 2112-2121, 2010.
Xiang P, Lo C, Argiropoulos B, Lai CB, Rouhi A, Imren S, Jiang X, Mager D, Humphries RK. Identification of E74-like factor 1 (ELF1) as a transcriptional regulator of the Hox cofactor MEIS1. Exp Hematol 38:798-808, 2010.
Rogers SL, Zhao Y, Jiang X, Eaves CJ, Mager DL and Rouhi A. Expression of the leukemic prognostic marker CD7 is linked to epigenetic modification in chronic myeloid leukemia. Mol Cancer 7: 41, 2010.
Kennah E, Ringrose A, Zhou LL, Esmailzadeh S, Qian H, Su MW, Zhou Y, Jiang X. Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells. Blood 113 (19): 4646-55, 2009.
Forrest DL, Jiang X, Eaves CJ & Smith CL. An approach to the management of chronic myeloid leukemia in British Columbia. Curr Oncol 15: 48-55, 2008.
Jiang X, Zhao Y, Forrest D, Smith C, Eaves A and Eaves C. Stem Cell Biomarkers in Chronic Myeloid Leukemia. Disease Markers 24:201-216, 2008.
Sheng G, Xu X, Lin Y-F, Wang C-E, Rong J, Cheng D, Peng J, Jiang X, Li S-H & Li X-J. Huntingtin-associated protein 1 interacts with Ahi1 to regulate cerebellar and brainstem development in mice. J Clin Invest 118: 2785-2795, 2008.
Zhou LL, Zhao Y, Ringrose A, DeGeer D, Kennah E, Lin AEJ, Sheng G, Li X-J, Turhan A & Jiang X. AH1-1 interacts with BCR-ABL and modulates BCR-ABL transforming activity and imatinib response of CML stem/progenitor cells. J Exp Med 205: 2657-2671, 2008.
Jiang X, Saw KM, Eaves A, & Eaves C. Instability of BCR-ABL gene in primary and cultured chronic myeloid leukemia stem cells. J Natl Cancer Inst 99 (9): 680-93, 2007.
Jiang X, Smith C, Eaves A, & Eaves C. The challenges of targeting chronic myeloid leukemia stem cells. Clin Lymphoma Myeloma 7 Suppl 2: S71-80, 2007.
Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, & Eaves C. Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 21 (5): 926-35, 2007.
Jorgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C, & Holyoake TL. Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 12 (2): 626-33, 2006.
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.
Zeng F, Chen MJ, Baldwin DA, Gong ZJ, Yan JB, Qian H, Wang J, Jiang X, Ren ZR, Sun D, & Huang SZ. Multiorgan engraftment and differentiation of human cord blood CD34+ Lin- cells in goats assessed by gene expression profiling. Proc Natl Acad Sci USA 103 (20): 7801-6, 2006.
Chalandon Y, Jiang X, Christ O, Loutet S, Thanopoulou E, Eaves A, & Eaves C. BCR-ABL-transduced human cord blood cells produce abnormal populations in immunodeficient mice. Leukemia 19 (3): 442-8, 2005.
Eisterer W, Jiang X, Christ O, Glimm H, Lee KH, Pang E, Lambie K, Shaw G, Holyoake TL, Petzer AL, Auewarakul C, Barnett MJ, Eaves CJ, & Eaves AC. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia 19 (3): 435-41, 2005.
Chalandon Y, Jiang X, Loutet S, Eaves AC, & Eaves CJ. Growth autonomy and lineage switching in BCR-ABL-transduced human cord blood cells depend on different functional domains of BCR-ABL. Leukemia 18 (5): 1006-12, 2004.
Jiang X, Zhao Y, Chan WY, Vercauteren S, Pang E, Kennedy S, Nicolini F, Eaves A, & Eaves C. Deregulated expression in Ph+ human leukemias of AHI-1, a gene activated by insertional mutagenesis in mouse models of leukemia. Blood 103 (10): 3897-904, 2004.
Eaves C, Jiang X, Eisterer W, Chalandon Y, Porada G, Zanjani E, & Eaves A. New models to investigate mechanisms of disease genesis from primitive BCR-ABL(+) hematopoietic cells. Ann N Y Acad Sci 996: 1-9, 2003.
Jiang X, Stuible M, Chalandon Y, Li A, Chan WY, Eisterer W, Krystal G, Eaves A, & Eaves C. Evidence for a positive role of SHIP in the BCR-ABL-mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia. Blood 102 (8): 2976-84, 2003.
Jorgensen HG, Allan EK, Jiang X, Liakopoulou E, Richmond L, Eaves CJ, Eaves AC, & Holyoake TL. Stage-specific alterations in serum levels of G-CSF in chronic myeloid leukaemia. Leukemia 17 (7): 1430-2, 2003.
Chalandon Y, Jiang X, Hazlewood G, Loutet S, Conneally E, Eaves A, & Eaves C. Modulation of p210(BCR-ABL) activity in transduced primary human hematopoietic cells controls lineage programming. Blood 99 (9): 3197-204, 2002.
Eisterer W, Jiang X, Bachelot T, Pawliuk R, Abramovich C, Leboulch P, Hogge D, & Eaves C. Unfulfilled promise of endostatin in a gene therapy-xenotransplant model of human acute lymphocytic leukemia. Mol Ther 5 (4): 352-9, 2002.
Holyoake TL, Jiang X, Drummond MW, Eaves AC, & Eaves CJ. Elucidating critical mechanisms of deregulated stem cell turnover in the chronic phase of chronic myeloid leukemia. Leukemia 16 (4): 549-58, 2002.
Jiang X, Ng E, Yip C, Eisterer W, Chalandon Y, Stuible M, Eaves A, & Eaves CJ. Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo. Blood 100 (10): 3731-40, 2002.
Jiang X, Hanna Z, Kaouass M, Girard L, & Jolicoeur P. Ahi-1, a novel gene encoding a modular protein with WD40-repeat and SH3 domains, is targeted by the Ahi-1 and Mis-2 provirus integrations. J Virol 76 (18): 9046-59, 2002.
Holyoake TL, Jiang X, Jorgensen HG, Graham S, Alcorn MJ, Laird C, Eaves AC, & Eaves CJ. Primitive quiescent leukemic cells from patients with chronic myeloid leukemia spontaneously initiate factor-independent growth in vitro in association with up-regulation of expression of interleukin-3. Blood 97 (3): 720-8, 2001.
Jiang X, Fujisaki T, Nicolini F, Berger M, Holyoake T, Eisterer W, Eaves C, & Eaves A. Autonomous multi-lineage differentiation in vitro of primitive CD34+ cells from patients with chronic myeloid leukemia. Leukemia 14 (6): 1112-21, 2000.
Holyoake T, Jiang X, Eaves C, & Eaves A. Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia. Blood 94 (6): 2056-64, 1999.
Jiang X, Lopez A, Holyoake T, Eaves A, & Eaves C. Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci U S A 96 (22): 12804-9, 1999.