Location: Cleveland Clinic Main Campus
We study multiple myeloma, the second most frequently diagnosed hematologic cancer in the United States. Many genes contain blueprints for proteins, but many others have the blueprints for molecules called miRNAs and noncoding RNAs that do not code for proteins. These miRNAs and noncoding RNAs, however, are quite important in regulating genes and are clearly involved in the development and progression of cancer, as well as other diseases.
Right now, we have several projects that focus on the roles of miRNA and noncoding RNAs in multiple myeloma. We are investigating how miRNA and noncoding RNAs initiate the growth and further development of multiple myeloma. In addition, we are identifying novel genes and miRNAs and noncoding RNAs involved in the development of multiple myeloma. Finally, because testing potential new drugs requires models that resemble the human disease as closely as possible, we are developing a new mouse model that recapitulates human multiple myeloma for preclinical studies.
My lab investigates the role of deregulated coding and noncoding genes in the initiation of multiple myeloma (MM), with the goal of designing new therapeutic strategies for MM. MM is a cancer characterized by proliferation of plasma cell colonies in the bone marrow. Increasingly, evidence shows that a super family of small (20~24 nt) non-coding RNAs, termed microRNAs (miRNAs), are involved in cell differentiation, proliferation, and apoptosis by targeting the 3’UTR of mRNAs of protein-coding genes, and therefore are involved in cancer pathogenesis, including MM. Currently, my research group is working on four projects related to this topic:
The long-term goal of the Zhao lab is to test novel therapy, potential diagnostic or prognostic markers and as therapeutic tools and targets to ultimately translate the knowledge gained to improved MM treatments.
Sadaf H, Hong H, Maqbool M, Emhoff K, Lin J, Yan S, Anwer F, Zhao J. Multiple myeloma etiology and treatment. Journal of Translational Genetics and Genomics. 2022, 6: 63-83.
Hu Y, Yang C, Amorim T, Maqbool M, Lin J, Li C, Fang C, Xue Li, Kwart A, Fang H, Yin M, Janocha AJ, Tsuchimoto D,Nakabeppu Y, Jiang X, Mejia-Garcia A, Anwer F, Khouri J, Qi X, Zheng QY, Yu JS, Yan S, LaFramboise T, AndersonKC, Herlitz LC, Munshi NC, Lin J, Zhao J. Cisplatin-mediated upregulation of apurinic/apyrimidinic endonuclease 2 (APE2) binding to myosin heavy-chain 9 (MYH9) provokes mitochondrial fragmentation and acute kidney injury. Cancer Research. 2021 Feb 1;81(3):713-723. doi: 10.1158/0008-5472.CAN-20-1010. Epub 2020 Dec 7. PMID: 33288657. PMCID: PMC7869671.
Hossain A, Lin Y, Driscoll G, Li J, Mcmahon A, Matos J, Zhao H, Tsuchimoto D, Nakabeppu Y, Zhao J, Yan S. APE2 is a general regulator of the ATR-Chk1 DNA damage response pathway to maintain genome integrity in pancreatic cancer cells. Frontiers Cell and Developmental Biology. 2021, 9:738502. PMCID: PMC8593216; PMID: 34796173.
Yang C, Lin J, Liang H, Xue L, Jiang M, Kwart A, Zhao J, Ren H, Jiang X, Munshi N. CD44 v5 domain Inhibition Represses the Polarization of Th2 Cell by Interfering with the IL-4/IL-4R Signaling Pathway. Immunol Cell Biol. 2021 Jul 5. doi: 10.1111/imcb.12491. Online ahead of print. PMID: 34219288
George LL, Deshpande SR, Cortese MJ, Kendall EK, Chattaraj A, Shah Z, Zhao J, Anwer F. Emerging Targets and Cellular Therapy for Relapsed Refractory Multiple Myeloma: A Systematic Review. Clinical Lymphoma, Myeloma and Leukemia. Published:June 14, 2021 DOI: https://doi.org/10.1016/j.clml.2021.06.003
Sewastianik T, Straubhaar JR, Zhao J, Samur MK, Adler K, Tanton H, Shanmugam V, Nadeem O, Dennis P, Pillai V, Wang J, Jiang M, Lin J, Huang Y, Brooks DJ, Bouxsein M, Dorfman D, Pinkus GS, Robbiani DF, Ghobrial IM, Budnik B, Jarolim P, Munshi NC, Anderson KC, Carrasco DR. miR-15a/16-1 deletion in activated B-cells promotes plasma cell and mature B-cell neoplasms. Blood. 2021 Jan 13:blood.2020009088. doi: 10.1182/blood.2020009088. PMID: 33751108
Huang H, Yu X, Han X, Hao J, Zhao J, Bebek G, Bao S, Prayson RA, Khalil AM, Jankowsky E, Yu JS. Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression. Cell Report. 2021 Jan 5;34(1):108522. doi: 10.1016/j.celrep.2020.108522.
Hu Y, Liu H, Fang C, Li C, Xhyliu F, Dysert H, Bodo J, Habermehl G, Russell B, Li W, Chappell M, Jiang X, Ondrejka S, Hsi E, Maciejewski JP, Yi Q, Anderson KC, Munshi NC, Ao G, Valent JN, Lin J, Zhao J. Targeting of CD38 by the Tumor Suppressor miR-26a Serves as a Novel Potential Therapeutic Agent in Multiple Myeloma. Cancer Research. 2020 May 15;80(10):2031-2044. doi: 10.1158/0008-5472.CAN-19-1077.Epub 2020 Mar 19. PMID: 32193289. PMCID: PMC7231653.
Hu B , Liu Y, Chen X, Zhao J, Han J, Dong H, Zheng Q, Nie G. Ferrostatin-1 protects auditory hair cells from cisplatin-induced ototoxicity in vitro and in vivo. Biochem Biophys Res Commun. 2020 Dec 17;533(4):1442-1448. PMID: 33109343.
Lin Y, McMahona A, Driscolla G, Bullocka S, Zhao J, Yan S. Function and molecular mechanisms of APE2 in genome and epigenome integrity. Mutation Research-Reviews in Mutation Research (MUTREV). 2020, 108347. Online ahead of print.
Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, Hassan H, Zhao J, Carew JS, Nawrocki ST, Anwer F. Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol. 2020 Sep 24. doi: 10.1111/ajco.13449. Online ahead of print.
Lin J, Hu Y, Zhao J. Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos. Jove. 2018 July 31. e58598, doi:10.3791/58598.
Hu Y, Lin J, Fang H, Fang J, Li C, Chen W, Liu S, Ondrejka S, Gong Z, Maciejewski J, Reu F, Yi Q, Zhao J. Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. Leukemia. 2018 Oct; 32(10):2250-2262. doi: 10.1038/s41375-018-0104-2. Epub 2018 Mar 22. PMID: 29632340. PMCID: PMC6151178. https://www.nature.com/articles/s41375-018-0104-2.
Lin J, Zhang W, Zhao J, Kwart AH, Yang C, Ma D, Ren X, Tai YT, Anderson KC, Handin RI, Munshi NC. A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy. Blood. 2016 Jul 14;128(2):249-52. doi: 10.1182/blood-2016-03-704460. PMID: 27207793.
Liu S, An J, Lin J, Liu Y, Bao L, Zhang W, Zhao J. Single nucleotide polymorphisms of microRNA processing machinery genes and outcome of hepatocellular carcinoma. Plos One. 2014 Mar 27;9(3):e92791.
Zhao J, Chu ZB, Hu Y, Lin J, Wang Z, Jiang M, Chen M, Wang X, Zhou Y, Chonghaile TN, Johncilla ME, Tai YT, Cheng JQ, Letai A, Munshi NC, Anderson KC, Carrasco RD. Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma. Cancer Research. 2015 Oct 15;75(20):4384-97.
Zhu D, Wang Z, Zhao J, Calimeri T, Meng J, Hideshima T, Fulciniti M, Kang Y, Ficarro SB, Tai YT, Hunter Z, McMillin D, Tong H, Mitsiades CS, Wu CJ, Treon SP, Dorfman DM, Pinkus G, Munshi NC, Tassone P, Marto JA, Anderson KC, Carrasco RD. The Cyclophilin A-CD147 complex promotes the proliferation and homing of multiple myeloma cells. Nature Medicine. 2015 Jun;21(6):572-80.
Zhao J, Carrasco DR. Crosstalk between microRNA30a/b/c/d/e-5p and the canonical Wnt pathway: implications for multiple myeloma therapy. Cancer Research. 2014 Oct 1;74(19):5351-8. (invited review)
Zhao J, Lin J, Zhu D, Wang X, Brooks D, Chen M, Chu ZB, Takada K, Ciccarelli B, Admin S, Tao J, Tai YZ, Treon S, Pinkus G, Kuo WP, Hideshima T, Bouxsein M, Munshi N, Anderson K, Carrasco DR. miR-30-5p functions as a tumor suppressor and novel therapeutic tool by targeting the oncogenic Wnt/β-catenin/BCL9 pathway. Cancer Research. 2014 Mar 15;74(6):1801-13.
Tian Z, Zhao J, Tai YZ, Amin S, Hu Y, Richardson PG, Anderson KC. Investigational agent MLN9708/2238 targets tumor-suppressor miR33b in MM cells. Blood. 2012 Nov 8;120(19):3958-67.
Takada K, Zhu D, Bird G, Sukhdeo K, Zhao J, Mani M, Lemieux M, Carrasco D, Horst D, Fulciniti M, Munshi N, Xu W, Kung A, Shivdasani R, Walensky L, Carrasco DR.Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling. Science Translational Medicine. 2012; 4:148, p. 148ra117.
Tai YT, Chang BY, Kong SY, Fulciniti M, Yang G, Calle Y, Hu Y, Lin J, Zhao J, Cagnetta A, Cea M, Sellitto MA, Zhong MY, Wang Q, Acharya C, Carrasco DR, Buggy JJ, Elias L, Treon SP, Matsui W, Richardson P, Munshi NC, Anderson KC. Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood. 2012 Aug 30;120(9):1877-87.
Lin J, Lwin T, Zhao J, Tam W, Choi YS, Moscinski LC, Dalton WS, Sotomayor EM, Wright KL, Tao J. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia. 2011, Jan;25(1):145-52.
Zhao J, Lin J, Lwin Tint, Guo J, Dalton SW, Sotomayor E, Tao J, Cheng JQ. microRNA expression profile and identification of miR-29 as a prognostic marker and pathogenetic factor by targeting CDK6 in mantle cell lymphoma. Blood. 2010, 1; 115(13): 2630-9.
Research Fellow Position Available: Our group is seeking highly motivated research fellows to join our studies to develop novel immune therapy for multiple myeloma. The position will provide a unique and multidisciplinary exposure to preclinical mouse models, molecular oncology, immune therapy, drug development and clinical trials. The ideal candidate has a MD or PhD degree in clinical medicine, biochemistry or molecular biology; has the appropriate expertise in mouse model is highly encouraged to apply. Outstanding verbal and communication skills are required. Interested applicants should submit a CV and contact information for 3 references to Dr. Jianjun Zhao via email: email@example.com
Drs. Yu and Zhao will study the role of a long non-coding RNA called Lucat1 in glioma stem cells in the search for new therapeutics to help treat glioblastoma and overcome treatment resistance.
The National Cancer Institute awarded Dr. Zhao $2.6 million dollars to continue research that seeks to develop treatment options for acute kidney injury that can commonly result as a side effect of chemotherapy.
Dr. Zhao and his team found that inhibiting the APE2 protein in a preclinical model of cisplatin-induced acute kidney injury significantly helped attenuate disease pathology.
Dr. Zhao found that sensitivity to daratumumab, an approved multiple myeloma treatment, may be rescued and restored using miR-26a.