My lab investigates the role of proteins and non-coding RNAs 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:
- We are analyzing the role of miRNAs and noncoding RNAs in MM initiation and progression using a genetically engineered mouse model and mouse model of human MM dissemination.
- We are functionally identifying the key downstream protein targets of miRNAs and noncoding RNAs related to MM progression.
- We are identifying and characterizing new miRNAs and noncoding RNAs related to MM initiation, progression, and drug resistance.
- We are developing a mouse model that recapitulates human MM for preclinical studies.
In other words ...
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.
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.
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.
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.
New findings from the lab of Jianjun Zhao, MD, PhD, may offer early hope for researchers and clinicians who have long been troubled by the challenge of treating patients with multiple myeloma, a cancer of plasma cells (a type of blood cell found in bone marrow that plays an important role in the immune system).
Lerner Research Institute’s Jianjun Zhao, MD, PhD, was recently awarded a two-year, $200,000 grant from the V Foundation for his research on the genetic underpinnings of multiple myeloma.