E3 ubiquitin ligase NKLAM/RNF19b suppresses myc-driven B cell lymphomagenesis in Eμ-myc mice.

Introduction: Natural Killer Lytic-Associated Molecule (NKLAM) (also known as RNF19b) is a membrane-bound E3 ubiquitin ligase. Previous studies demonstrated a role of NKLAM in natural killer (NK) cell function and pro-inflammatory cytokine production by macrophages. Studies using lymphoma, melanoma and breast cancer cells found that tumor dissemination and metastasis are greater in NKLAM-deficient knockout (KO) mice than in wild type (WT) mice, indicating that NKLAM participates in controlling tumor development Methods: We employed the Eμ-myc mouse model to determine whether NKLAM influences B cell lymphomagenesis. In young Eμ-myc mice, overexpression of myc in B lineage cells leads to expansion of non-neoplastic precursor B cells, which subsequently disappear. Over time, pre-B, pro-B or immature B cell lymphomas develop. Results: NKLAM KO Eμ-myc mice have higher levels of precursor B cells than WT transgenic mice. These cells express more myc and Bcl-2 and persist longer. Lymphomas develop more rapidly in NKLAM KO Eμ-myc mice and strikingly, have a more differentiated phenotype, characterized by surface IgM. These lymphomas are also less aggressive than IgM- tumors when injected into non-transgenic mice. Infusion of NKLAM+ immune cells into young NKLAM KO Eμ-myc mice extends their survival, which increases the proportion of mice that develop more aggressive, immune-resistant IgM- lymphomas. Discussion: These studies indicate that NKLAM contributes to both the early and late phases of myc-driven B cell lymphomagenesis, first by limiting expression of myc and Bcl-2 within the non-malignant pre-B cells, resulting in longer tumor-free survival. This is followed by immunoediting by NKLAM+ immune cells, leading to development of IgM- lymphomas that are less immunogenic and more aggressive.