The prognostic marker NRIP1 is associated with tumor progression and immune infiltration in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy characterized by high relapse rates and treatment resistance, highlighting the need for novel biomarkers to improve clinical outcomes. In this study, we explore the roles of nuclear receptor-interacting protein 1 (NRIP1) in AML, focusing on its associations with tumor progression and immune infiltration. Analysis of public AML gene expression datasets reveals that NRIP1 expression is significantly increased in AML patients. Those with high NRIP1 expression have markedly shorter overall survival than those with low expression. Furthermore, NRIP1 expression is significantly associated with the infiltration of diverse immune cells, including B cells, dendritic cells, T cells, mast cells, eosinophils, and T helper cells, suggesting that NRIP1 may be a regulator of immune cell infiltration. Functional enrichment analysis indicates that NRIP1 and its interacting partners are involved in tumorigenesis, immune microenvironment remodeling, and metabolic reprogramming. Survival analysis confirms the prognostic value of NRIP1. Importantly, functional validation in AML cell lines confirms that NRIP1 knockdown suppresses proliferation and induces apoptosis. Our study identifies NRIP1 as a multifaceted regulator that promotes AML by driving tumor progression, regulating immune cell infiltration, and modulating ferroptosis, highlighting its role as a novel prognostic biomarker.

1. Introduction

Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy characterized by clonal expansion of hematopoietic stem cells, impaired differentiation, and evasion of apoptosis [1]. Despite advances in treatment modalities such as chemotherapy, hematopoietic stem cell transplantation, and immunotherapy, the 5-year survival rate for adult AML patients remains dismal at approximately 24% [2]. These limitations underscore the urgent need for a deeper understanding of AML pathogenesis and the identification of novel prognostic biomarkers and therapeutic targets.

The initiation, progression, and relapse of AML are driven not only by acquired genetic mutations [3] but also by the dynamic interplay between leukemic cells and the tumor microenvironment (TME) [4,5]. The bone marrow TME in AML, comprising an altered extracellular matrix, immunosuppressive immune cells, and soluble factors, fosters a protective niche that undermines conventional and immune-based therapies. Consequently, overcoming this immunosuppressive environment is crucial for enhancing therapeutic efficacy.

Nuclear receptor-interacting protein 1 (NRIP1), also known as RIP140, is a multifaceted transcriptional coregulator that modulates the activity of multiple transcription factors and nuclear receptors [6]. Its roles as either an oncogene or a tumor suppressor have been documented in several solid tumors, including breast [7,8], colon [9], and liver [10] cancers. For instance, in breast cancer, NRIP1 promotes tumor progression by regulating interferon gamma signaling [7] and glycolytic metabolism [8]. Previous studies have demonstrated that NRIP1 is highly expressed in hematopoietic stem cells and that its expression level is correlated with prognosis in patients with chronic lymphocytic leukemia (CLL) [11]. Furthermore, the oncogenic potential of NRIP1 can be unleashed not only through transcriptional upregulation but also through genetic alterations, as exemplified by the recent identification of the NRIP1::PDGFRB fusion gene in pediatric Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) [12]. This fusion constitutively activates the tyrosine kinase PDGFRB, driving leukemogenesis and thereby representing a novel therapeutic target. Moreover, a NRIP1-MIR99AHG fusion transcript accompanied by a genomic inversion was recently discovered in patients with chronic myelomonocytic leukemia (CMML), suggesting its potential role in the biology and progression of this disease [13]. These findings highlight that NRIP1 is not merely a passive biomarker but also a central, active driver of leukemogenesis through structural rearrangements.

Furthermore, therapy resistance remains a major hurdle in AML treatment. Recent studies have highlighted the critical roles of diverse signaling pathways and metabolic reprogramming in mediating chemoresistance. For instance, the AHR signaling pathway has been shown to contribute to cytarabine resistance by enhancing mitochondrial oxidative phosphorylation [14]. These findings highligh