title: Targeting the miR-221-222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma.
abstract: Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma, intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. miRNAs are noncoding small RNAs that play important roles in the regulation of gene expression and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone-induced drug resistance in multiple myeloma using the isogenic cell lines MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely proapoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain-of-function and loss-of-function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to dexamethasone, whereas anti-miR-221-222 partially restored the dexamethasone sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in multiple myeloma drug resistance and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming dexamethasone resistance in patients. The clinical utility of this approach is predicated on the ability of antisense miR-221-222 to increase survival while reducing tumor burden and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of multiple myeloma. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in multiple myeloma cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zhang-Bo
authors.initials: ZB
authors.lastname: Chu
authors.affiliation: Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Lin
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Meng
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Bioinformatics, School of Life Science and Technology, Tongji University, Shanghai, China.
authors.forename: Xujun
authors.initials: X
authors.lastname: Wang
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Yangsheng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Triona
authors.initials: T
authors.lastname: Ni Chonghaile
authors.affiliation: Department of Pathology, Brigham & Women's Hospital, Boston, MA.
authors.forename: Melanie E
authors.initials: ME
authors.lastname: Johncilla
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Jin Q
authors.initials: JQ
authors.lastname: Cheng
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Antony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.|Boston VA Healthcare System, Boston, MA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.|Department of Pathology, Brigham & Women's Hospital, Boston, MA.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; D003907:Dexamethasone; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C494772:BAK1 protein, human; C438378:BBC3 protein, human; C525709:MIR221, human; C525710:MIR222, human