Overexpression of PAX5 induces apoptosis in multiple myeloma cells

Abstract

PAX5 is an essential transcription factor for the commitment of lymphoid progenitors to the B-lymphocyte lineage. PAX5 suppression results in retrodifferentiation of B lymphocytes to an uncommitted progenitor cell stage, whereas PAX5 suppression in mature B lymphocytes leads to further development into plasma cells. Here, we have analyzed the fate of plasma cell lines following PAX5 reexpression. Human B cell lines were infected with Ad5/F35 adenoviruses encoding either EYFP or PAX5. Expression analysis of specific plasma cell transcription factors (IRF4, Blimp-1 and XBP-1) suggests that PAX5 reexpression does not induce retrodifferentiation of plasma cells into B lymphocytes. Interestingly, the viability of RPMI-8226 and U266 multiple myeloma cell lines markedly declined at 4-7 days post-transduction, whereas other plasma cell lines maintained their viability. Apoptosis analysis through Annexin V measurement also revealed a higher level of apoptosis in PAX5-expressing myeloma cell lines. Finally, Western blot analysis of pro- and anti-apoptotic proteins revealed that the anti-apoptotic protein MCL-1 was down-modulated in PAX5-transduced multiple myeloma cell lines. In conclusion, our results show that the expression of PAX5 in plasma cell lines induces apoptosis exclusively in multiple myelomas. This might represent a potential therapeutic avenue in the treatment of multiple myeloma.

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders

“…Although overexpression of PAX5 has been reported to trigger nondrug-induced apoptosis in multiple myeloma cells (Proulx et al, 2010), our data suggest that PAX5 increases Bortezomib-induced NF-κB activation and drug-resistance by enhancing RIP2 Ser176 phosphorylation. Meanwhile, Bortezomib-induced apoptosis in primary multiple myeloma and leukemia cells has been proven to be related to PAX5 expression.…”

PAX Genes in Cancer; Friends or Foes?

“…In hepatocellular carcinoma PAX5 has been identified as a novel tumor suppressor through interacting with the p53 signaling pathway (Liu et al, 2011). Consistent with this, overexpression of PAX5 induces apoptosis in multiple myeloma cells (Proulx et al, 2010). PAX5 is expressed in medulloblastoma (Kozmik et al, 1995), and in a sub-type of neuroblastoma (Baumann Kubetzko et al, 2004), perhaps reflecting the earlier requirement for PAX5 expression in the mid/hindbrain boundary during embryogenesis (Urbanek et al, 1994).…”

The Pax-5 Gene: A Pluripotent Regulator of B-cell Differentiation and Cancer Disease

“…The observation of interregulating capabilities between Pax-5 variants has also been made in murine models (23). A link between Pax-5 expression and apoptosis was also revealed in a study of multiple myeloma cell lines, in which the authors found that Pax-5 overexpression promoted apoptosis events (24). Other studies suggest a growth-inhibitory function for Pax-5.…”