Polymorphism in ANRIL is associated with relapse in patients with multiple myeloma after autologous stem cell transplant.
Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells and overproduction of monoclonal immunoglobins. Treatment with melphalan is currently standard of care for younger and fit patients when followed by hematopoietic stem cell transplantation (HSCT), and in transplant ineligible patients when used in combination regimens. It has been previously shown that changes in the p53 pathway are associated with melphalan efficacy, but the regulatory role of the p14ARF-MDM2-p53 axis has yet to be fully explored. Recently, a non-coding RNA, ANRIL (antisense non-coding RNA in the INK4-ARF locus) has been shown to negatively regulate the transcription of the entire INK4-ARF locus and simultaneously modulate the p53 and pRb pathways. Moreover, some single nucleotide polymorphisms (SNPs) in ANRIL have previously been associated with susceptibility to several malignancies. Here we investigated select ANRIL SNPs in DNA from patient-derived peripheral blood mononuclear cells obtained from 108 MM patients treated with high-dose melphalan followed by HSCT. Our results show that the rs2151280 (CàT) SNP in ANRIL was associated with worse progression-free survival (TC/CC vs TT: HR = 0.53, 95%CI, [0.26, 1.07], P = 0.07; adjusted HR = 0.39, 95%CI, [0.18, 0.84], P = 0.016), and the TT variant had higher ANRIL expression and lower p15, p14ARF, and p16 expression compared to the TC/CC variants. Our results indicate that ANRIL may be involved in melphalan-mediated apoptosis via down-regulating p14ARF and subsequent p53, and that the rs2151280 polymorphism may be a potential prognostic biomarker for relapse in melphalan-treated MM patients.
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio.|Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Ming J
MJ
Poi
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Junan
J
Li
Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Douglas W
DW
Sborov
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Zachary
Z
VanGundy
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Yu Kyoung
YK
Cho
Department of Nursing, The Ohio State University Wexner Medical Center, Columbus, Ohio.
Misty
M
Lamprecht
The Briskin Myeloma Center, Division of Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope, Duarte, California.
Flavia
F
Pichiorri
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio.
Mitch A
MA
Phelps
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio.
Craig C
CC
Hofmeister
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008558:Melphalan / Q000009:adverse effects; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D062085:RNA, Long Noncoding / Q000235:genetics*; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D015996:Survival Rate; D014182:Transplantation, Autologous; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; C561518:CDKN2B antisense RNA, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D062085:RNA, Long Noncoding; D025803:Tumor Suppressor Protein p14ARF; D008558:Melphalan
ANRIL; disease relapse; melphalan; multiple myeloma; single nucleotide polymorphism