Hypoxia reduces CD138 expression and induces an immature and stem cell-like transcriptional program in myeloma cells

Abstract

Although CD138 expression is a hallmark of plasma cells and myeloma cells, reduced CD138 expression is occasionally found. However, the mechanisms underlying CD138 downregulation in myeloma cells remain unclear. Previous reports suggest that the bone marrow microenvironment may contribute to CD138 downregulation. Among various factors in the tumor microenvironment, hypoxia is associated with tumor progression, poor clinical outcomes, dedifferentiation and the formation of cancer stem cell niches in solid tumors. Since recent findings showed that progression of multiple myeloma (MM) delivers hypoxia within the bone marrow, we hypothesized that CD138 expression may be regulated by hypoxia. In the present study, we examined whether the expression of CD138 and transcription factors occurred in myeloma cells under hypoxic conditions. MM cell lines (KMS-12BM and RPMI 8226) were cultured under normoxic or hypoxic conditions for up to 30 days. Changes in the phenotype and the expression of surface antigens and transcription factors were analyzed using flow cytometry, RT-PCR and western blotting. All-trans retinoic acid (ATRA) was used to examine the phenotypic changes under hypoxic conditions. The expression levels of CD138, CS1 and plasma cell-specific transcription factors decreased under hypoxic conditions, while those of CD20, CXCR4 and B cell-specific transcription factors increased compared with those under normoxic conditions. Stem cell-specific transcription factors were upregulated under hypoxic conditions, while no difference was observed in ALDH activity. The reduced CD138 expression under hypoxic conditions recovered when cells were treated with ATRA, even under hypoxic conditions, along with decreases in the expression of stem cell-specific transcription factor. Interestingly, ATRA treatment sensitized MM cells to bortezomib under hypoxia. We propose that hypoxia induces immature and stem cell-like transcription phenotypes in myeloma cells. Taken together with our previous observation that decreased CD138 expression is correlated with disease progression, the present data suggest that a hypoxic microenvironment affects the phenotype of MM cells, which may correlate with disease progression.

Hypoxia-inducible KDM3A addiction in multiple myeloma

“…For personal use only on March 25, 2019. by guest www.bloodadvances.org From under chronic hypoxia and prevents cell proliferation and cell maturation. Expression of IRF4 is suppressed in hypoxic environments, 7,9 although IRF4 is a key factor in promoting myeloma oncogenesis. 16 Therefore, it is likely that during hypoxia, factors that contribute to myeloma cell survival may act independent of IRF4.…”

“…It has been reported that myeloma cells change their surface antigens and metabolic pathways in response to hypoxic stress, and they also acquire drug resistance. 7,8 In addition, we recently reported that miR-210, whose expression is markedly elevated in a hypoxic environment, downregulates IRF4 through the direct regulation of an 18S rRNA base methyltransferase, DIMT1. 9 These findings led us to conclude that miR-210 suppresses IRF4 expression .…”

“…[6][7][8][9] These reports are based on the following concept: Gene expression in myeloma cells in the BM microenvironment is distinct from that in the other BM regions. The oxygen pressure of BM is lower than that in the peripheral blood, but higher than that in the BM microenvironment, which may result in different gene expression profiles between BM and the BM microenvironment.…”

“…Indeed, hypoxia causes myeloma cells to acquire different phenotypes when compared with normoxia. [6][7][8][9] Hypoxia can suppress myeloma cell proliferation, inhibit differentiation, and cause resistance to apoptosis. Although a variety of gene expression changes occur in cancer cells during hypoxia, there may be master regulators that are common to all cancer subtypes; namely, hypoxia-inducible factor-1a (HIF-1a) and HIF-2a.…”

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

“…8,26 Hypoxia promotes immature and stem-cell like phenotype in myeloma cells by decreasing CD138 and increasing CD34 expression. 9,39 Such hypoxic cells are resistant to proteasome inhibitors including bortezomib and carfilzomib. 9 In accordance to these studies, our results showed that hypoxic RPMI8226 and U266 cells became resistant to bortezomib compared to their normoxic counterparts.…”