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Research_

Cancer and Stem Cell Laboratory

Targeting malignant stem cells towards a cure for blood cancer
Our lab is investigating how healthy stem cells are converted into malignant stem cells and is developing effective therapies to destroy cancer stem cells without harming healthy stem cells for curing deadly blood cancer.

Blood cancer could be the leading form of cancer deaths by 2035, according to Australia's first strategic action plan.

Acute myeloid leukemia is the deadliest form of blood cancer with a high rate of treatment failure and relapse. Relapsed leukemia has an extremely poor survival of <10%.

Chemotherapy is the first-line treatment for the deadly blood cancer. However, it is not effective against dormant (inactive) malignant stem cells that consequently regenerate a more aggressive leukemia using their unique tumorigenic/stemness characteristics. Ablating leukemia stem cells is critical for successful anticancer therapy.

Over the past 9 years, our lab has generated a body of knowledge in the discovery of therapeutic targets essential for leukemia stem cell characteristics and established evidence of therapeutic efficacy for clinical trials. Most of our research has been published in top scientific journals including Cancer Cell and Blood.

In partnership with industry and close collaboration with clinicians, we are currently converting our research breakthroughs into innovative stem cell-targeted therapies in clinical trials, which will directly benefit patients with the deadly blood cancer.

  • Stem cell mechanisms
  • Targeted therapies
  • Precision medicine
  • Biomarker discovery
  • Cancer metabolism
  • Signaling pathway
  • Epigenetics
  • Noncoding RNA
  • Programmed cell death
  • National Health and Medical Research Council (NHMRC)
  • Cancer Australia
  • Leukaemia Foundation
  • Cancer Council
  • Tour de Cure
  • Industry
  • Teng L, Feng YC, Guo ST, Wang PL, Wang SX, Zhang SN, Qi TF, La T, Zhang YY, Zhao XH, Zhang D, Wang JY, Shi Y, Li JM, Cao H, Liu T, Thorne RF, Jin L, Shao F, Zhang XD. The pan-cancer lncRNA PLANE regulates an alternative splicing program to promote cancer pathogenesis. Nature Communications. 2021. 12:3734. (IF 14.92)
  • Chen J, Nelson C, Wong M, Tee AE, Liu PY, La T, Fletcher JI, Kamili A, Mayoh C, Bartenhagen C, Trahair TN, Xu N, Jayatilleke N, Wong-Erasmus M, Peng H, Atmadibrata B, Cheung BB, Lan Q, Bryan TM, Mestdagh P, Vandesompele J, Combaret V, Boeva V, Wang JY, Janoueix-Lerosey I, Cowley MJ, MacKenzie KL, Dolnikov A, Li J, Polly P, Marshall GM, Reddel RR, Norris MD, Haber M, Fischer M, Zhang XD, Pickett HA, and Liu T. Targeted therapy of TERT-rearranged neuroblastoma with BET bromodomain inhibitor and proteasome inhibitor combination therapy. Clinical Cancer Research. 2021. 27(5):1438-1451. (IF 12.53)
  • Lan Q, Liu PY, Bell JL, Wang JY, Hüttelmaier S, Zhang XD, Zhang L, Liu T. The emerging roles of RNA m6A methylation and demethylation as critical regulators of tumorigenesis, drug sensitivity, and resistance. Cancer Research. 2021. 81(13):3431-3440. (IF 12.7)
  • Salik B, Yi H, Hassan N, Santiappillai N, Vick B, Connerty P, Duly A, Trahair T, Woo AJ, Beck D, Liu T, Spiekermann K, Jeremias I, Wang J, Kavallaris M, Haber M, Norris MD, Liebermann DA, D'Andrea RJ, Murriel C, Wang JY. Targeting RSPO3-LGR4 signaling for leukemia stem cell eradication in acute myeloid leukemia. Cancer Cell. 2020. 38:263-278. (IF 31.74)
  • Hassan N, Yang J and Wang JY. An improved protocol for establishment of AML patient-derived xenograft models. STAR Protocols. 2020. 1(3):100156. doi: 10.1016/j.xpro.2020.100156Yang J, Hassan N, Chen SXF, Datuin J, Wang JY. Self-renewal pathways in acute myeloid leukemia stem cells. In Pier Paolo Piccaluga (Eds.), Acute Leukemias. Rijeka, Croatia: InTech Publishers. Book Chapter. 2020. doi:10.5772/intechopen.94379.
  • Lynch JR, Salik B, Connerty P, Vick B, Leung H, Pijning A, Jeremias I, Spiekermann K, Trahair T, Liu T, Haber M, Norris MD, Woo AJ, Hogg P, Wang J and Wang JY. JMJD1C-mediated metabolic dysregulation contributes to HOXA9-dependent leukemogenesis. Leukemia. 2019. 33:1400-1410. (IF 11.53   
  • Gonzales-Aloy E, Connerty P, Salik B, Liu B, Woo AJ, Haber M, Norris MD, Wang J and Wang JY. miR-101 suppresses the development of MLL-rearranged acute myeloid leukemia. Haematologica. 2019. 104:296-299. (IF 9.94)
  • Wong M, Sun Y, Xi Z, Milazzo G, Poulos RC, Bartenhagen C, Bell JL, Mayoh C, Ho N, Tee AE, Chen X, Li Y, Ciaccio R, Liu PY, Jiang CC, Lan Q, Jayatilleke N, Cheung BB, Haber M, Norris MD, Zhang XD, Marshall GM, Wang JY, Hüttelmaier S, Fischer M, Wong JWH, Xu H, Giovanni Perini, Qihan Dong, George RE, Liu T. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nature Communications. 2019. 10:3319. (IF 14.92)
  • Liu P, Tee A, Milazzo G, Hannan K, Maag J, Mondal S, Atmadibrata B, Bartonicek N, Peng H, Ho N, Mayoh CM, Ciaccio R, Sun Y, Henderson M, Gao J, Everaert C, Hulme A, Cheung B, Shi L, Wang JY, Simon T, Fischer M, Zhang XD, Marshall G, Norris M, Haber M, Vandesompele J, Li J, Mestdagh P, Hannan R, Dinger M, Perini G, and Liu T. The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35. Nature Communications. 2019. 10:5026. (IF 14.92)
  • Woo AJ, Patry C, Ghamari A, Pregernig G, Zheng K, Piers T, Hibbs M, Li JK, Fidalgo M, Wang JY, Lee J, Leedman PJ, Wang J, Fraenkel E, and Cantor AB. Zfp281 (ZBP-99) plays a functionally redundant role with Zfp148 (ZBP-89) during erythroid development. Blood Advances. 2019. 3:2499-2511. (IF 6.799)
  • Wong MK, Tee AE, Milazzo G, Bell JL, Poulos RC, Atmadibrata B, Sun Y, Jing D, Ho N, Ling D, Liu PY, Zhang XD, Hüttelmaier S, Wong JW, Wang JY, Polly P, Perini G, Scarlett CJ, Liu T. The histone methyltransferase DOT1L promotes neuroblastoma by regulating gene transcription. Cancer Research. 2017. 77:2522-2533. (IF 12.7)
  • Sun Y, Atmadibrata B, Yu D, Wong MKK, Liu B, Ho N, Ling D, Tee AE, Wang JY, Mungrue IN, Liu PY, Liu T. Up-regulation of LYAR induces neuroblastoma cell proliferation and survival. Cell Death & Differentiation. 2017. 24:1645-1654. (IF 15.83)
  • Lynch JR, Yi H, Casolari DA, Voli F, Gonzales-Aloy E, Fung TK, Liu B, Brown A, Liu T, Haber M, Norris MD, Lewis ID, So CWE, D’Andrea RJ, Wang JY. Gaq signaling is required for the maintenance of MLL-AF9 induced acute myeloid leukemia. Leukemia. 2016. 30:1745-1748. (IF 11.53)
  • Lynch JR, Wang JY. G protein-coupled receptor signaling in stem cells and cancer. Int J Mol Sci. 2016. 17:707. (IF 5.92)
  • Dietrich PA, Yang C, Leung HH, Lynch JR, Gonzales E, Liu B, Haber M, Norris MD, Wang J, Wang JY. GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis. Blood. 2014. 124:3284-3294. (IF 23.63)
  • Lane SW*, Wang JY*, Lo Celso C*, Ragu C, Bullinger L, Sykes SM, Ferraro F, Shterental S, Lin CP, Gilliland DG, Scadden DT, Armstrong SA, Williams DA. Differential niche and Wnt requirements during acute myeloid leukemia progression. Blood. 2011. 118:2849-2856. *equal contribution (IF 23.63)
  • Wang JY, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, Zon LI, Armstrong SA. The Wnt/β-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010. 327:1650-1653. (IF 47.73)
  • Wang JY, Armstrong SA. Cancer: inappropriate expression of stem cell programs. Cell Stem Cell. 2008. 2: 297-299. (IF 24.63)
  • Wang JY, Armstrong SA. Genome-wide SNP analysis in cancer: leukemia shows the way. Cancer Cell. 2007. 11:308-309. (IF 31.74)
  • Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang JY, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006. 442:818–822. (IF 49.96)

Current projects

Acute myeloid leukemia (AML) is a difficult-to-treat blood cancer with a 5-year survival rate of only 27.4% in Australia.

Despite intensive chemotherapy, the majority of patients with AML relapse and ultimately die from their disease.

Clinical evidence has supported the important role of leukemia stem cells in the high relapse rate of AML patients. Leukemia stem cells reside in a mostly quiescent state and as such they are resistant to chemotherapy.

These cells possess several unique features such as self-renewal and escaping from cell death. Targeted elimination of leukemia stem cells is now believed to be essential for AML patients to achieve a complete remission.

Our studies have identified key self-renewal pathways (Science 2010; Blood 2014; Leukemia 2016, 2019; Cancer Cell 2020) for stem cell formation and our exciting new findings of pathway inhibitors provide promising therapeutic opportunities to specifically target leukemia stem cells.

This project is designed to understand the mechanisms of action of pathway inhibitors in order to develop effective stem cell-targeted therapies that will benefit patients suffering from treatment resistance and disease relapse.

Epigenetic regulation of gene expression plays crucial roles in stem cell functions.

Inappropriate maintenance of epigenetic ‘marks’ - that sit on the nuclear DNA of cancer cells and control the activity of genes - results in activation of oncogenic self-renewal pathways leading to the formation of malignant stem cells and the subsequent development of cancer.

Unlike genetic alterations, epigenetic marks can be reversed by treatments with chromatin-modifying drugs, making them suitable targets for epigenetic-based therapies. Our studies have uncovered key epigenetic regulators that contribute to cancer formation and progression.

This project aims at exploring epigenetic mechanisms that govern malignant stem cell function and at discovering chromatin-modifying drugs that are capable of reversing cancer-associated epigenetic marks.

The outcome of this study will have the potential to develop innovative epigenetic therapies.

The recent discovery of non-coding RNAs (ncRNAs) has dramatically altered our view of gene regulation in cancer. MicroRNAs (miRNAs) are a class of ncRNAs that function to regulate gene expression at the transcriptional and post-transcriptional level, playing a pivotal role in cancer progression and metastasis.

Using an integrated miRNA-mRNA expression profiling analysis, we have documented a miRNA regulatory network, whose downregulation is associated with the aggressive phenotype of cancer (Haematologica 2019).

This study will investigate how a crosstalk between miRNA regulatory network and epigenetic/signaling pathways determines the fate of stem cells and this will pave the way for developing novel RNA-based therapeutics in effectively destroying malignant stem cells.

Techniques: Single cell multi-omics technologies (transcriptomics, proteomics and epigenomics), cell-based assays, drug response assays, molecular and cell biology, gene and protein expression, immunofluorescence, gene editing, chromatin immunoprecipitation sequencing (ChIP-seq), flow cytometry, patient-derived xenograft mouse models, in vivo preclinical drug testing, stem cell technologies etc.

Significance: Successful completion of these projects will generate new insights into cancer and stem cell biology, identify novel therapeutic targets, and provide preclinical validation of therapeutic potential.

These studies therefore have the potential to lead to the development of novel therapies that directly and selectively kill cancer stem cells, which are now considered to be the root cause of disease progression, tumor resistance to chemotherapy, and ultimate relapse.

Lead researcher

Dr Jenny Wang
Dr Jenny Wang
Academic profile