Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Abstract

Mutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging pre-clinical data for the use of trametinib in SETBP1-mutant disease.

Identification of ferroptosis‐related genes as potential biomarkers of tongue squamous cell carcinoma using an integrated bioinformatics approach

“…HRAS, NRAS, and KRAS, collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer; the relationship between oncogenic RAS and ferroptosis is still controversial [43]. As the phosphorylation gene of MAPK protein, NRAS has become one of the taxonomic markers of four subtypes of melanoma [44]; moreover, high expression of NRAS is associated with poor prognosis of lung adenocarcinoma [45]. Tumor extracellular vesicles carrying miR-125b-5p enter diffuse large B-cell lymphoma (DLBCL) cells and target TNFAIP3, thereby reducing the sensitivity of DLBCL to rituximab [46], and overexpression of TNFAIP3 is associated with a lower survival rate in breast cancer patients [47]; a study about ferroptosis after cerebral hemorrhage also find TNFAIP3 upregulation [48].…”

The impact of SETBP1 mutations in neurological diseases and cancer

“…The SETBP1 p.G870N mutation co-exists frequently with JAK3 mutations and is associated with a poor prognosis (Wakamatsu et al, 2021). In JMML, SETBP1 enhances NRAS gene expression, causing the activation of mitogen-activated protein kinase signaling and repression of differentiation (Carratt et al, 2021). MDS with mutations in U2FA1 gene, which encodes U2 small nuclear RNA auxiliary factor 1, is associated with a poor prognosis and is prone to mutations in SETBP1 (H. Wang et al, 2020).…”