title: Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.
abstract: Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Adil Doganay
authors.initials: AD
authors.lastname: Duru
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Nanotechnology Research and Application Center, Sabanci University, Istanbul, Turkey.
authors.forename: Tolga
authors.initials: T
authors.lastname: Sutlu
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Wallblom
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Uttervall
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lund
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Stellan
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Gösta
authors.initials: G
authors.lastname: Gahrton
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Evren
authors.initials: E
authors.lastname: Alici
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D000069286:Bortezomib / Q000627:therapeutic use*; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D053319:Tumor Necrosis Factor Decoy Receptors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; C451501:TNFRSF10D protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D000069286:Bortezomib