Bortezomib-resistant nuclear factor κB expression in stem-like cells in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is a subtype of B-cell Non-Hodgkin's Lymphoma (NHL) and accounts for approximately 6% of all lymphomas. Unlike small lymphocytic lymphoma and chronic lymphocytic lymphoma, which are relatively sensitive to chemotherapy, MCL is highly refractory to most chemotherapy, and has the worst survival rate among NHL patients. Stem-like cells in MCL, which we have termed mantle cell lymphoma-initiating cells (MCL-ICs), enriched in the population that are lack of prototypic B-cell marker CD19. These cells were able to self-renew upon serial transplantation and are highly tumorigenic. Importantly, these stem-like cells confer chemotherapeutic resistance to MCL. In this report, we show that stem-like MCL-ICs are resistant to bortezomib, as well as chemotherapeutic regimens containing bortezomib, despite constitutive nuclear factor-κB (NF-κB) expression. Interestingly, bortezomib treatment induced MCL-IC differentiation in plasma-like cells with upregulated expression of CD38 and CD138. This process was accompanied by expression of plasma cell differentiation transcriptional factors, BLIMP-1 and IRF4. This article is the first to show that stem-like MCL cells utilize constitutive NF-κB expression for survival. Given that the NF-κB expression in MCL-ICs is resistant to bortezomib, it will be important to find alternative therapeutic strategies to inhibit NF-κB expression.
Centre for Stem Cell Research, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas-Health Science Center at Houston, Houston, TX 77030, USA.
Hyun Joo
HJ
Jung
Zheng
Z
Chen
Luis
L
Fayad
Michael
M
Wang
Jorge
J
Romaguera
Larry W
LW
Kwak
Nami
N
McCarty
D018941:Antigens, CD19 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human