Mantle cell lymphoma activation enhances bortezomib sensitivity.
Patients with mantle cell lymphoma (MCL) typically respond to initial treatment but subsequently relapse. This pattern suggests that a population of MCL cells is both drug resistant and capable of clonogenic growth. The intracellular enzyme retinaldehyde dehydrogenase (ALDH) provides resistance to several toxic agents. ALDH can also identify stem cells in normal adult tissues and tumorigenic cancer stem cells in several human malignancies. We studied ALDH expression in MCL and found small populations of ALDH(+) cells that were highly clonogenic. Moreover, ALDH(+) MCL cells were relatively quiescent and resistant to a wide range of agents. Normal B cells can be activated by specific unmethylated cytosine-phosphate-guanosine (CpG) DNA motifs through toll-like receptor 9, and we found that the synthetic CpG oligonucleotide 2006 (CpG) reduced the frequency of quiescent ALDH(+) MCL cells, induced terminal plasma cell differentiation, and limited tumor formation in vitro and in vivo. Treatment with CpG also significantly enhanced the activity of the proteasome inhibitor bortezomib that was associated with induction of the unfolded protein response. Our data suggest that CpG may target clonogenic and resistant ALDH(+) cells as well as improve the activity of proteasome inhibitors in MCL.
Brennan
Sarah K
SK
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Meade
Brooke
B
Wang
Qiuju
Q
Merchant
Akil A
AA
Kowalski
Jeanne
J
Matsui
William
W
D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D020522:Lymphoma, Mantle-Cell / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D050697:Retinal Dehydrogenase; D051217:Toll-Like Receptor 9 / Q000276:immunology; D056811:Unfolded Protein Response / Q000187:drug effects
D001897:Boronic Acids; C408982:CPG-oligonucleotide; D007527:Isoenzymes; D009838:Oligodeoxyribonucleotides; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051217:Toll-Like Receptor 9; D000069286:Bortezomib; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D046988:Proteasome Endopeptidase Complex