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B-cell transcription factor PAX5 functions as a tumor suppressor by regulating the cell cycle in primary effusion lymphoma

ABSTRACT: Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma arising from Kaposi sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 (HHV-8) infection. PEL shows invasive behavior, causing body cavity effusions without apparent solid tumors. The typical prognosis and clinical course of patients with PEL are poor and potentially lethal. Clarification of the pathogenic mechanisms of PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers such as CD19, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. PAX5 is expressed from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via methylation of the PAX5 promoter region. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To clarify the in vivo function of PAX5, we analyzed the restoration of PAX5 in a PEL xenograft model using severely immunodeficient, NOD/SCID/Jak3-deficient (NOJ) mice. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has a critical role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic approach for patients with PEL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160276 | GEO | 2024/08/02

REPOSITORIES: GEO

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