Journal Article

Decreased PU.1 expression in mature B cells induces lymphomagenesis

Komohara, Yoshihiro, Ueno, Niina, Matsuoka, Masao, Endo, Shinya, Shichijo, Takafumi, Carreras, Joaquim, Yuki, Hiromichi, Nishimura, Nao, Ueno, Shikiko, Sato, Ai, Miyaoka, Masashi, Kawano, Yawara, Nakamura, Naoya, Yasunaga, Jun‐ichirou, Hirata, Shinya, Nosaka, Kisato, Mitsuya, Hiroaki, Tatetsu, Hiro, Tenen, Daniel G., Ando, Kiyoshi, Akashi, Koichi, Okuno, Yutaka, Toyoda, Kosuke

2024

Overview

Diffuse large B‐cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non‐Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non‐germinal center B‐cell‐like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1‐Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B‐cell lymphomas. In contrast, no wild‐type mice developed B‐cell lymphoma. In addition, RNA‐seq analysis of lymphoma cells from Cγ1‐Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral‐transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B‐cell lymphoma development. PU.1, particularly the non‐germinal center B‐cell‐like (GCB) type, is downregulated in human lymphoma cells. Conditional knockout of Spi1 in mature B cells induces B cell lymphoma in mice.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Analysis / Animals / Antibodies / Apoptosis / B cells / B-cell lymphoma / B-Lymphocytes - metabolism / Cell cycle / Cell Line, Tumor / Cloning / Complementarity-determining region 3 / diffuse large B‐cell lymphoma / DLBCL / Ethylenediaminetetraacetic acid / ETS protein / Gene Expression Regulation, Neoplastic / Genes / Genetic analysis / Genomes / Germinal centers / Hematology / Hodgkin's lymphoma / Humans / Immunodeficiency / Immunoglobulins / Immunohistochemistry / Laboratory animals / Leukemia / Lymphadenopathy / Lymphocytes B / Lymphoid cells / Lymphoma / Lymphoma, Large B-Cell, Diffuse - genetics / Lymphoma, Large B-Cell, Diffuse - metabolism / Lymphoma, Large B-Cell, Diffuse - pathology / lymphomagenesis / Medical colleges / Medical research / Medicine, Experimental / Mice / Mice, Knockout / Multiple myeloma / Myeloma / Non-Hodgkin's lymphomas / Nucleotide sequence / Original / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / PU.1 / PU.1 protein / RNA / Spi1 / Splenomegaly / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription factors / Tumor cells / Tumor suppressor genes / Tumors