Bortezomib resistance in mantle cell lymphoma is associated with plasmacytic differentiation.
Bortezomib induces remissions in 30%-50% of patients with relapsed mantle cell lymphoma (MCL). Conversely, more than half of patients' tumors are intrinsically resistant to bortezomib. The molecular mechanism of resistance has not been defined. We generated a model of bortezomib-adapted subclones of the MCL cell lines JEKO and HBL2 that were 40- to 80-fold less sensitive to bortezomib than the parental cells. Acquisition of bortezomib resistance was gradual and reversible. Bortezomib-adapted subclones showed increased proteasome activity and tolerated lower proteasome capacity than the parental lines. Using gene expression profiling, we discovered that bortezomib resistance was associated with plasmacytic differentiation, including up-regulation of IRF4 and CD38 and expression of CD138. In contrast to plasma cells, plasmacytic MCL cells did not increase immunoglobulin secretion. Intrinsically bortezomib-resistant MCL cell lines and primary tumor cells from MCL patients with inferior clinical response to bortezomib also expressed plasmacytic features. Knockdown of IRF4 was toxic for the subset of MCL cells with plasmacytic differentiation, but only slightly sensitized cells to bortezomib. We conclude that plasmacytic differentiation in the absence of an increased secretory load can enable cells to withstand the stress of proteasome inhibition. Expression of CD38 and IRF4 could serve as markers of bortezomib resistance in MCL. This study has been registered at http://clinicaltrials.gov as NCT00131976.
Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Patricia
P
Pérez-Galán
Helena
H
Mora-Jensen
Marc A
MA
Weniger
Arthur L
AL
Shaffer
Edgar G
EG
Rizzatti
Colby M
CM
Chapman
Clifton C
CC
Mo
Lawrence S
LS
Stennett
Christoph
C
Rader
Poching
P
Liu
Nalini
N
Raghavachari
Maryalice
M
Stetler-Stevenson
Constance
C
Yuan
Stefania
S
Pittaluga
Irina
I
Maric
Kieron M
KM
Dunleavy
Wyndham H
WH
Wilson
Louis M
LM
Staudt
Adrian
A
Wiestner
D051997:ADP-ribosyl Cyclase 1 / Q000096:biosynthesis; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D000099218:Interferon Regulatory Factor-4
D051997:ADP-ribosyl Cyclase 1; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D050835:Interferon Regulatory Factors; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines; D000099218:Interferon Regulatory Factor-4