The current risk stratification of AML patients relies on chromosomal variants and genetic mutations, categorizing them into high risk, intermediate risk, and low risk. However, these conventional prediction tools have mainly focused on the intrinsic characteristics of cancer, ignoring the contribution of TME to cancer development[26]. Recently, the involvement of tumor-associated neutrophils, a key component of the TME, has become increasingly prominent in cancer progression. Tumor-infiltrating neutrophils exhibit pro-carcinogenic effects and predict poor prognosis in bladder urothelial cancer[27]. Furthermore, peripheral NLR has emerged as a potential prognostic factor in various solid tumors[28] [29] [30] [31], as well as in certain hematological malignancies such as non-Hodgkin lymphoma and multiple myeloma[32, 33]. Additionally, neutrophils have been implicated in influencing the efficacy of immunotherapy and mediating resistance to radiation therapy[34]. In this study, we investigated the effect of neutrophil-related genes on AML prognosis and explored a potential prediction system. Importantly, CD37 was identified as a critical neutrophil-related gene associated with adverse AML prognosis.
Advancements in next-generation sequencing (NGS) technology have revolutionized our ability to access the genomic profiles of cancer, aiding in precise cancer classification and prognosis prediction. In this study, we focused on investigating the prognostic role of neutrophil-related genes in AML. Our analysis revealed that eight neutrophil-related genes—CSF3R, LST1, ITGAX, BRAF, FFAR2, CD300A, ITGAL, and CD37—exhibited strong correlations with the prognosis of AML. By integrating five of these genes, we constructed an effective prognostic model. Notably, a significant prevalence of acquired CSF3R mutations has been observed in patients with severe congenital neutropenia during the pre-leukemia stage, progressing to overt AML or myelodysplastic syndrome (MDS)[35]. Intriguingly, there is a high incidence of transformation to MDS or AML in patients who harbor acquired CSF3R mutations, suggesting the importance of CSF3R in the pathogenesis and prognosis of AML[36]. BRAF gene, belonging to the RAF kinase family, plays pivotal roles in transmitting growth signals in physiological pathways[37, 38]. As a critical constituent of the MAPK pathway, BRAF has been detected as driver mutation in several tumor types, including melanoma, non-small cell lung cancer (NSCLC), and anaplastic thyroid cancer (ATC). Consequently, BRAF has emerged as an appealing target for therapeutic inhibition[39].
Activation of FFAR2 by microbiota-derived metabolites has been shown to decrease the proliferation of leukemic cells in vitro[40]. Moreover, FFAR2 itself impacts leukemia cell growth in vivo[41]. Deletion of FFAR2 compromises the immunosuppressive capabilities of MDSCs on T cells within the tumor microenvironment[42]. CD300A, also recognized as CMRF-35 or IRp60, belongs to the CD300 cell surface molecule superfamily[43], which plays a critical role in modulating immune function and contributes to the host response against various diseases, including infectious diseases[44, 45], cancer[46], and allergy[47, 48]. The expression levels of CD300A were associated with risk stratification and the clinical relevance of AML. Elevated CD300A expression may serve as an independent adverse prognostic indicator for OS and relapse-free survival (RFS) in AML[49]. Furthermore, CD300A is involved in regulating neutrophil recruitment, IL-1β production, and participates in the processes of neutrophil apoptosis and efferocytosis[50].
CD37, belonging to the transmembrane 4 superfamily (TM4SF), is a tetraubiquitin protein prominently expressed on B cell surfaces. CD37 promotes neutrophil adhesion and recruitment by enhancing cytoskeletal function downstream of integrin-mediated adhesion processes[51]. This characteristic makes CD37 an attractive molecular target for immunotherapy against B-cell lymphomas and leukemias[52]. AML patients with high CD37 expression were shown to have shorter OS and disease-free survival (DFS)[53]. While previous studies primarily analyzed CD37 survival data from TCGA datasets, our study extended this analysis by incorporating three additional independent AML datasets and two AML prognostic models. Our investigation provided a comprehensive evaluation of the prognostic relevance of CD37 in AML, confirming its association with poorer outcomes. The consistent findings across multiple datasets and prognostic models underscore CD37's potential as a promising biomarker for assessing cancer risk in AML patients. However, the precise mechanism of CD37 in AML remains to be fully elucidated.
CD37 plays a pivotal role in cancer immunity. Our study unveiled a significant correlation between CD37 expression and gene signatures associated with immune regulation in AML. These signatures encompassed various aspects such as leukocyte-mediated immunity, regulation of immune effector processes, negative regulation of the immune system and inhibition of T cell proliferation. Furthermore, the multifaceted involvement of CD37 protein in diverse biological processes including cell adhesion, motility, differentiation, proliferation, metastasis, growth, survival, trafficking, intercellular communication via exosomes, and immune responses is widely acknowledged[54]. Additionally, CD37 interacts with key proteins such as integrins, immune receptors, and signaling molecules, which serve as regulators for leukocyte activation, motility, and antigen presentation[55].
Emerging studies suggest the pivotal role of CD37 in regulating B-cell survival and shaping immune evasion. Specifically, tumors with high expression of CD37 demonstrate increased infiltration by various immune cell subsets, compared to those with lower CD37 expression levels. It has been known that AML patients commonly present with dysfunctional T cells and NK cells at diagnosis[56, 57]. In our investigation, we observed an augmented presence of immunosuppressive cells such as MDSC, Treg cells and NK cells in the high CD37 expression group. Moreover, the elevated ratio of CD4+ T cells to CD8+ T cells suggests an immunosuppressive leukemic microenvironment. This milieu facilitates AML blast evasion from immune surveillance and collaborates to promote disease progression, which might explain the poorer outcomes observed in individuals with high CD37 expression. Furthermore, CD37 may play a role in orchestrating the dysfunction of antitumor immune cells. Our analysis also reveals enrichment of gene sets associated with CD4+ T cells, naive T cells, naive CD8+ T cells, naive B cells and naive CD4+ T cells in the high CD37 expression group. However, further investigations are warranted to elucidate the precise mechanisms by which CD37 influences the development and activation of immune cells.
ICIs therapies, which rejuvenate the effective antitumor immune response mediated by T cells, have revolutionized cancer treatment. Our research indicates a positive association of CD37 expression with T-cell dysfunction scores in AML. High CD37 expression predicts a more favorable response to immunotherapy. Additionally, CD37 correlates positively with inhibitory immune checkpoints like PD1, CTLA4, CD86, and LAG3, which are often overexpressed in AML cells, presenting promising therapeutic targets. Furthermore, our study reveals a positive correlation between CD37 and MHC class II molecules. The complexes of tetraspanins MHC class II molecules exhibit enrichment with the CD86 co-stimulatory molecule and the HLA-DM peptide editor[58]. We propose that CD37 regulates peptide presentation on MHC molecules, potentially influencing T-cell activation. Collectively, these findings suggest CD37 as a potential biomarker for AML immunotherapy.
In summary, we developed a prognostic model for AML incorporating five neutrophil-related genes, demonstrating its potential independent prognostic significance. Moreover, we identified a robust link between CD37 expression and immune response in AML. However, the validation of our findings is constrained by insufficient data. Increased clinical samples and prospective studies are necessary to confirm the predictive efficacy of the neutrophil-based model in real-world clinical scenarios. The underlying mechanism of neutrophil-related genes within tumor microenvironment remains ambiguous and requires further exploration in future studies.