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CD9, a tetraspanin in cancer: biology and therapeutic ...
Abstract Tetraspanins are transmembrane proteins that organize into functional structures known as tetraspanin-enriched microdomains, where they coordinate interactions with key partner proteins and modulate cellular processes such as adhesion, signaling, and
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Abstract
Tetraspanins are transmembrane proteins that organize into functional structures known as tetraspanin-enriched microdomains, where they coordinate interactions with key partner proteins and modulate cellular processes such as adhesion, signaling, and motility. Among them, CD9 is a widely expressed member, also recognized as a classical marker of exosomes. Beyond its role in development and tissue homeostasis, CD9 has emerged as a modulator of the crosstalk between cancer cells and their microenvironment. It can contribute to processes such as cell migration, invasion, and resistance to therapy. Mechanistically, CD9 interacts with many partners including integrins, metalloproteinases, and signaling receptors to influence cell behavior. However, its functional contribution to tumor progression remains controversial. While CD9 expression is associated with enhanced dissemination in certain cancers, it appears to restrain motility and invasion in others. This likely reflects the complexity of its context-dependent functions, influenced by cell type, microenvironmental cues, and molecular partners. A deeper understanding of the regulatory mechanisms is therefore essential. In this review, we overview the tetraspanin family and summarize current knowledge on CD9 regulation and function across cancers, with a focus on leukemia. While its role in tumorigenesis remains debated, CD9 is a reliable biomarker of leukemic cells and can be used for diagnosis and MRD monitoring in acute lymphoblastic and myeloid leukemia, particularly in patients lacking molecular markers. We also discuss emerging therapeutic strategies that aim to target CD9 in cancer.
CD9 gene regulation in cancer, and biological implication in acute lymphoblastic leukemia. Created with BioRender.com.
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Introduction
Tetraspanins (TSPANs), a family of transmembrane proteins, play a central role in mediating interactions between cancer cells and microenvironment by contributing to the organization of the cellular membranes. Among them, TSPAN29, also known as cluster of differentiation 9 (CD9), interacts with specific partners, including other tetraspanins and adhesion or junctional proteins, to form “tetraspanin webs” that support partner-dependent functions [1, 2]. CD9 is involved in various physiological and pathological processes, depending on the cell type and associated molecular partners.
As an organizer of the plasma membrane, CD9 influences both the architecture of tetraspanin-enriched microdomains and signaling pathways such as TNF-α and TGF-β, which are key regulators of tissue development and homeostasis. One of the most well-characterized functions of CD9 is its role in sperm-egg membrane fusion. CD9 modulates the adhesion strength of spermatozoa to the oocyte, notably through its interaction with integrin α6β1, the receptor for ADAM2 on the sperm membrane [3]. The tspan29 invalidation in mice does not impact viability or development; however, it leads to female infertility due to defective sperm-egg membrane fusion, while male fertility remains unaffected [4].
Accumulating evidence links CD9 to cancer invasion, metastasis, and drug resistance through its regulation of cell adhesion, extracellular matrix (ECM) degradation, and extracellular vesicle production [5, 6]. However, its precise role in cancer progression remains controversial. The functional impact of CD9 appears to be context-dependent, varying according to tumor type, expression of interacting partners, and microenvironmental conditions. Contradictory findings have been reported across cancer types, and even within the same malignancy, including leukemia.
This review aims to synthesize current knowledge regarding the role of CD9 in cancer, with a particular focus on whether CD9 functions solely as a biomarker potentially amenable to therapeutic targeting, or as an active contributor to disease progression, particularly in leukemogenesis.
Tetraspanins
Structure and functions
Tetraspanins were first described in 1981 as transmembrane glycoproteins localized both on the plasma membrane and within various intracellular organelles [7]. These proteins are ubiquitously expressed across human cell types and constitute a large family comprising at least 33 members in humans, designated Tspan1 to Tspan33, although multiple nomenclatures have historically been used to classify them [8]. Their structural features, chromosomal localization, and the conservation of specific residues across species suggest that tetraspanin genes originated from duplication events of a common ancestral gene [9]. Tetraspanins are composed of several distinct domains that mediate diverse biological functions [2, 10]. The four transmembrane helices are highly conserved among species and between tetraspanins, reflecting their essential role in tetraspanin-tetraspanin interactions (Fig. 1). The two extracellular domains, one short (known as the short extracellular loop, SEL or EC1) and one long (known as the long extracellular loop, LEL or EC2), exhibit lower sequence homology between species and tetraspanin members. The LEL contains four to eight highly conserved cysteine residues that form disulfide bonds stabilizing its tertiary structure, along with a hypervariable region that enables specific interactions with partner proteins.
Fig. 1: Structure of tetraspanin, example of CD9.Tetraspanins are proteins composed of 4 transmembrane domains and 2 extracellular loops containing a variable number of cysteine residues that form disulfide bridges. Various post-translational modifications can be found. Created with BioRender.com.
The intracellular N- and C-terminal domains are well conserved across species but differ significantly between tetraspanin family members, suggesting that they perform fundamental yet distinct functions. These domains mediate interactions with cytoskeletal components and other proteins involved in various signal cell signaling pathways. The C-terminal domain also contains peptide motifs that guide the subcellular localization of tetraspanins to specific compartments. Post-translational palmitoylation, particularly within the transmembrane regions, plays a key role in stabilizing tetraspanin interactions and in assembling them into functional structures known as tetraspanin-enriched microdomains (TEMs) [10, 11]. Within the plasma membrane, tetraspanins cluster with various partner proteins to form these large and dynamic complexes. Co-immunoprecipitation studies have identified both direct interactions with transmembrane, extracellular, or cytosolic proteins and indirect associations within multiprotein complexes. These interactions enable tetraspanins to regulate cellular functions by bringing partners into close proximity, thereby creating a complex and dynamic functional platform termed the “tetraspanin web” [12, 13]. Tetraspanins associate with a wide range of partners, including adhesion molecules such as integrins (α3β1, α4β1, and α6β1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and epithelial cell adhesion molecule (EpCAM1) [14]. They also interact with growth factor receptors, members of the immunoglobulin superfamily (e.g., EWI-F, EWI-2) [15, 16], enzymes such as peptidases, and signaling proteins including PKC, PLCγ, PI4KII, and G-proteins. Additionally, other molecules such as cholesterol and gangliosides contribute to the stabilization of tetraspanin complexes [8, 17]. Several N-glycosylation sites within the LEL domain enhance protein stability by preventing enzymatic degradation, increasing hydrophilicity, supporting proper folding, and contributing to quality control mechanisms.
Tetraspanins play a crucial role in maintaining cellular homeostasis [18]. They are involved in a range of essential cellular processes, particularly adhesion and migration, which are fundamental during development and in tissue physiology. Moreover, tetraspanins are implicated in various pathological conditions [12]. For example, loss of TSPAN26 (also known as CD37) has been shown to trigger the spontaneous development of diffuse large B-cell lymphoma in mouse models [19]. Deletions of TSPAN6 gene have been reported in patients with epilepsy and intellectual disability [20]. Similarly, TSPAN7, which is highly expressed in brain, has been associated with neurological disorders, including autism spectrum disorder and intellectual disability, and also plays an important role in immune regulation in patients with type 1 diabetes [21,22,23,24].
Tetraspanin 29
To identify markers of human hematopoietic precursors and lymphoblasts, Kersey et al. immunized mice with the NALM6, a relapse-derived pre-B acute lymphoblastic leukemia (ALL) cell line. They subsequently isolated an antibody targeting a 24 kDa cell surface antigen [7]. This antigen, initially referred to as Leukemia-Associated Cell Surface Antigen p24, is also known as Motility-Related Protein-1, TSPAN29, or CD9. CD9 is broadly expressed across a wide range of hematopoietic and non-hematopoietic cell types, including epithelial cells, endothelial cells, neurons, smooth muscle cells, oocytes, and stromal cells. It is also frequently expressed in malignant cells.
At the subcellular level, CD9 is found at the plasma membrane, in endocytic compartments, and within extracellular vesicles (EVs), where it is often enriched in highly curved membrane regions such as microvillar-like projections and filopodia [25, 26]. Depending on the cell type and its interacting partners, CD9 is involved in a variety of physiological and pathological processes, including cell-cell contact, interactions with the ECM, integrin-dependent adhesion and migration, signal transduction, membrane fusion, cell proliferation, apoptosis, inflammation, infection, survival, and tumor progression [27, 28]. Its ability to interact with other tetraspanins as well as diverse transmembrane and intracellular proteins, and thereby modulate their function, has earned it the designation of “molecular facilitator” [14, 29]. Although several physiological functions of CD9 have been identified, many remain incompletely understood and should require further investigation within each specific cellular context.
The CD9 gene is located on chromosome 12p13.31. It spans 38,557 base pairs, comprises 13 exons, and encodes a protein of 228 amino acids [1, 2]. The CD9 protein contains four transmembrane segments, short cytoplasmic N- and C-terminal domains, and two extracellular (EC) domains: a short loop (EC1) and a larger loop (EC2) (Fig. 1) [30]. The EC2 domain is stabilized by two disulfide bridges involving conserved cysteine residues, including the characteristic CCG motif shared by all tetraspanins. The EC1 domain harbors a potential N-glycosylation site located near the second transmembrane segment. Additionally, multiple cysteine residues at the cytoplasmic and transmembrane domains undergo palmitoylation, a post-translational modification essential for membrane organization and protein functionality [1, 2, 25, 30].
Regulation of CD9 expression in healthy and cancer cells
Several studies have identified complex and multilayered mechanisms regulating CD9 expression at the epigenetic, transcriptional, post-transcriptional, translational, and post-translational levels. This intricate regulation underscores the functional significance of CD9. However, the precise regulatory mechanisms remain incompletely understood and warrant further investigation.
Epigenetic regulation
The promoter of CD9 is highly enriched in cytosine and guanine nucleotides (74%) and contains 37 CpG sites, suggesting that DNA methylation level may play a significant role in the regulation of its transcriptional activity. CD9 expression has been shown to be regulated by promoter methylation in multiple myeloma (MM) and non-small cell lung cancer (NSCLC) cells, where hypermethylation leads to transcriptional silencing [31]. Treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza) restores CD9 expression in MM cells [32, 33]. However, the inability of 5-aza to induce CD9 re-expression in all cell lines suggests that CpG methylation is not the sole epigenetic regulation involved, and other mechanisms, such as histone modification, showed a much stronger reactivation of CD9 expression in MM. More recently, a study using neuroblastoma cell lines reported a strong association between high CD9 promoter methylation and advanced disease stage, reinforcing the role of epigenetic regulation in cancer progression (invasion and metastasis) in neuroblastoma [34]. Chromatin immunoprecipitation (ChIP-qPCR) assays demonstrated that the proto-oncogene MYCN represses CD9 transcription. Since MYCN can recruit histone deacetylases (HDACs), the potential involvement of HDAC5 was evaluated. HDAC5 was shown to bind to the CD9 promoter and repress its transcription. Furthermore, combined treatment with 5-aza and HDAC inhibitors (HDACi) synergistically reactivated CD9 expression in neuroblastoma and small cell lung cancer cells. These findings suggest that CD9 expression can be modulated through epigenetic drug targeting, with potential therapeutic benefits of combining DNA methyltransferase and HDAC inhibitors. But the underlying mechanisms must be more complex than it seems and regarded with caution in each subtype of cancer. Indeed, while overexpression of CD9 promotes the development of bone metastases in human breast cancer cells [35], it has the opposite effect in melanoma cells [36].
Epigenetic alterations are major driver of deregulated gene expression in carcinogenesis. Although the role of CD9 in cancer development remains controversial, its expression appears closely linked to chromatin compaction. Overexpression of CD9 reflects a more relaxed chromatin state, potentially facilitating the expression of other genes involved in carcinogenesis, including proto-oncogenes or tumor suppressors, depending on the cancer type. To date, data on the epigenetic regulation of CD9 in leukemia cells remain limited. While speculative, it is plausible that mechanisms described in other malignancies may also operate in leukemia, highlighting the need for further investigation [32]. In this context, the loss of CD9 expression in ETV6/RUNX1-positive B acute lymphoblastic leukemia (B-ALL), which usually has a more favorable prognosis compared with other subtypes, could reflect general increased promoter methylation or chromatin modifications [37,38,39].
Transcriptional regulation
The CD9 promoter lacks canonical TATA and CAAT boxes, which are typically associated with transcriptional initiation, suggesting a more complex regulatory model. Transcription of CD9 may be initiated from multiple sites within the promoter region [40]. The promoter harbors several binding sites for the transcription factor Sp1 within a G/C-rich region, as well as consensus motifs for NF-κB and members of the Krox/EGR zinc finger protein family. Reporter gene assays have confirmed transcriptional initiation within the promoter region spanning –237 to –154 bp [36, 41]. Sp1 binds specifically to the 5’ end of the –237 to –205 bp region. Gel retardation assays revealed binding of an unknown factor to the −205 to –154 bp segment, potentially corresponding to the transcription factor AP2, as suggested by the presence of a consensus AP2-binding site [42]. These findings support that AP2 may cooperate with Sp1 to activate CD9 transcription, as demonstrated in both melanoma and leukemic cells [36, 41]. Additionally, the transcription factor grainyhead-like 1 (GRHL1) has been implicated in CD9 regulation. In neuroblastoma cells, GRHL1 binding to the CD9 promoter was demonstrated by ChIP-qPCR, and its repression led to decreased CD9 expression [34].
In NK cells, CD9 expression has been shown to be sensitive to oxygen availability, with increased levels observed under hypoxic conditions [43, 44]. Our team identified hypoxia-response elements (HREs) within the CD9 promoter and demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) binds to these HREs, positively regulating CD9 expression in pediatric B-ALL [45]. Given that HIF1A can recruit chromatin-modifying enzymes such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), this suggests that the epigenetic regulation of CD9 in cancer cells may also be influenced by the tissue localization and microenvironment of the considered cells.
Post-transcriptional regulation
Loss of CD9 expression has been associated with progression and metastasis in prostatic adenocarcinoma [46]. While both normal and malignant prostate cells express wild-type CD9 mRNA, tumor cells additionally harbor CD9 transcript variants with internal deletions. Immunohistochemical analyses have confirmed decreased CD9 protein expression in adenocarcinomas carrying these variants. The three deleted regions are not attributable to conventional alternative splicing, as they lack canonical splice donor and acceptor sites. Instead, these deletions appear to arise from a novel RNA alteration mechanism. Notably, the nucleotides at the start of the deleted regions are identical to those where the RNA sequence resumes, implicating a potential role for repetitive elements in generating these variants. As the deletions affect large extracellular and intracellular domains critical for CD9 interactions, these transcript variants are likely to impair its function [46].
In Merkel cell carcinoma and squamous cell carcinoma of the tongue, CD9 loss has also been associated with enhanced metastatic potential [47]. Characterization of the 5′ untranslated region (5′UTR) of CD9 mRNA identified two major transcript variants differing only in 5′UTR length (3 vs. 102 nucleotides). In silico analyses of the longer variant predicted a secondary structure that impedes ribosomal scanning, thereby blocking translation. Quantitative analysis revealed not only reduced CD9 mRNA, but also a shift toward the long 5′UTR isoform in CD9-negative cells. Although this translational block remains to be experimentally confirmed, these findings support a post-transcriptional mechanism regulating CD9 expression in these carcinomas.
More recently, miR-518f-5p has been identified as a microRNA that modulates CD9 expression in prostate cancer cells [48]. It binds to the CD9 5′UTR, leading to reduced CD9 expression in both non-tumorigenic and tumorigenic prostate cells. This downregulation increased migration and reduced ECM adhesion in normal cells, while inducing the opposite phenotype in cancer cells. Overexpression of miR-518f-5p drastically increased proliferation in normal cells but had no effect on the proliferation of tumor cells. Although the mechanistic link between CD9 expression and migration/adhesion remains unclear, these findings reveal a miRNA-dependent regulatory layer with differential effects on normal and malignant cell behavior [48, 49].
CD9 expression and function during hematopoiesis
Hematopoietic differentiation
Global gene expression profiling of the murine multipotent hematopoietic FDCP-mix cell line identified CD9 as a marker of primitive hematopoietic cells [50]. In the mouse bone marrow (BM), long-term hematopoietic stem cells (LT-HSCs) have a high CD9 expression that decreases in short-term (ST)-HCSs and multipotent progenitors (MPPs) [51]. Further study demonstrated its ability to enrich HSCs [52]. In mouse BM, CD9 is expressed by myeloid cells and a subset of lymphocytes, while erythroid cells are largely negative for its expression [4]. In peripheral blood, CD9 is detected on neutrophils, megakaryocytes, platelets, and specific lymphocyte subsets. Despite this broad expression pattern across hematopoietic lineages, CD9 deficiency does not appear to significantly affect the composition of hematopoietic populations in vivo [4, 53]. In human BM, CD9 displays a complex expression pattern across hematopoietic cell populations. It is heterogeneously expressed on CD34-positive stem/progenitor cells, with expression levels varying from low to high, depending on the degree of lineage commitment [54, 55]. Other studies are more cut-and-dried and report that the most primitive HSCs, defined as CD34-positive/CD38-negative, display low or undetectable CD9 expression [56, 57]. CD9 is variably expressed on mature leukocytes, including activated T lymphocytes, natural killer cells, and dendritic cells, as well as on mature myelo-monocytic cell lineage such as monocytes, macrophages, basophils, eosinophils, megakaryocytes, and platelets [58, 59]. Similar to murine erythrocytes, human erythrocytes also lack CD9 expression [54].
Early reports showed that targeting CD9 with antibodies triggers platelet aggregation, likely through its association with glycoprotein GPIIb/IIIa (integrin αIIb/β3 or CD41/CD61), with which it co-localizes in intracellular compartments and activation zones on the platelet membrane [60,61,62]. This aggregation could be prevented by inhibitors of the thromboxane pathway, implicating CD9 as a signal-initiating molecule involved in platelet activation via phospholipase C [63,64,65]. Additionally, CD9 blockade reduced the megakaryocytic differentiation of human CD34-positive cells, as evidenced by loss of expression of early and late megakaryocyte (MK) markers and increase of the number of colony-forming unit-MK (CFU-MK) progenitors unable to differentiate. These findings highlight the critical role of CD9 in megakaryopoiesis and platelet activation, likely through its contribution to membrane remodeling [54, 66].
During B-cell development, CD9 is highly expressed in CD10-positive B-cell precursors in the BM and is subsequently downregulated as these cells mature into CD10-negative B lymphocytes, which migrate into the peripheral blood [67]. This pattern suggests that CD9 may contribute to the retention of hematopoietic precursors within the BM niche. Notably, CD9 can be re-expressed in plasma cells, further supporting its involvement in hematopoietic cell differentiation.
CD9 is also highly expressed on mesenchymal stem cells (MSCs), which serve as essential regulators of hematopoiesis by providing factors that support HSC survival, proliferation, and differentiation. CD9 blockade showed impaired myeloid differentiation of hematopoietic progenitors [51]. However, in long-term murine BM cocultures, inhibition of CD9 only on MSCs is sufficient to impair myeloid cell production from HSCs, reducing hematopoietic cell viability, proliferation, and differentiation [68,69,70]. These findings suggest that CD9 contributes to stromal-hematopoietic interactions critical for myeloid maturation within the BM microenvironment. However, functional in vivo validation (e.g., CD9 knockdown/knockout specifically in MSCs) is still lacking, and, as noted above, CD9 deficiency has not been associated with overt defects in hematopoietic populations.
Homing and migration of stem cells
CD9 mediates physical interactions between stromal and hematopoietic cells by contributing to pro-adhesive signaling. CD9 blockade with antibodies promoted the migration of HSCs beneath the MSC layer in coculture experiments [68]. Given that both cell types express CD9, authors pretreated solely MSCs with the anti-CD9 antibodies. Results showed an increased HSCs adhesion relative to controls, which indicates a crucial role of CD9 on the stromal component. Exposure to CXCL12, a chemokine abundantly secreted by MSCs, upregulates CD9 expression on CD34-positive hematopoietic cord blood cells in vitro via CXCR4 signaling, involving activation of G-protein, protein kinase C, phospholipase C, extracellular signal-regulated kinase (ERK), and Janus kinase 2 pathways [55]. CD34-positive cells pretreated with anti-CD9 antibodies exhibited reduced CXCL12-induced migration while adhesion was enhanced in vitro. In vivo, CD9-positive cells demonstrated superior engraftment capacity in immune-deficient mice compared to CD9-negative cells. Notably, CD9 expression was upregulated in engrafted cells and CD9 blockade abolished engraftment by CD34-positive cells. Overall, these data highlight the implication of CD9 in HSC homing and retention within the BM niche.
Cell adhesion
Cell adhesion and migration are tightly regulated processes involving adhesion receptors, such as integrins, that form specialized complexes mediating responses to extracellular signals [71]. CD9 plays a pivotal role in these processes, particularly during lymphocyte diapedesis by facilitating adhesion to endothelial cells (Fig. 2). On the endothelial side, CD9 promotes the assembly and membrane stabilization of vascular adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1), thereby supporting leukocyte-endothelial adhesion [72]. On leukocytes, CD9 participates in the scaffolding of integrins and other adhesion molecules within TEMs, enabling firm adhesion to the endothelium [14]. Transient CD9 depletion in endothelial cells reduced membrane expression of ICAM-1 and VCAM-1, suggesting that CD9 may facilitate their trafficking and/or membrane retention. The transient depletion of CD9 also diminished CXCL12-induced transendothelial migration and adhesion strength of lymphocytes [73].
Fig. 2: Role and partners of CD9 in cell adhesion and migration.A During diapedesis, CD9 interacts with integrins, which then bind to adhesion proteins on the surface of endothelial cells or to molecules in the ECM. In this way, signaling pathways such as the RAC1 pathway can be activated or inhibited. B In order to initiate cell migration, CD9 interacts with proteins such as CXCR4 to activate signaling pathways at the origin of migration or with metalloproteinases, which then degrade the ECM, clearing a pathway to facilitate cell migration. Created with BioRender.com.
In antigen-presenting cells, CD9 enhances the adhesive and co-stimulatory functions of the activated leukocyte cell adhesion molecule (ALCAM/CD166) by scaffolding it within TEMs, promoting its interaction with CD6 on T cells [14, 74]. CD9 also associates with integrins such as α4β1 on T lymphocytes, facilitating the accumulation of its high-affinity form at the immune synapse and the activation of integrin-dependent ERK1/2 signaling [14, 75]. Additionally, CD9 can interact with laminin-binding integrins (α2β1, α3β1, α6β1, α6β4) and fibronectin-binding integrins (α5β1), modulating adhesion to the ECM [76]. CD9 may also directly bind fibronectin through its EC2 loop, or via α5β1 integrin, leading to focal adhesion destabilization. Conversely, CD9 depletion restored focal adhesion nucleation, marked by vinculin and paxillin clustering, with minimal α2β1 integrin presence [77]. In pre-B cells, CD9 blockade promoted adhesion to BM fibroblasts through VLA-4 (α4β1) and VLA-5 (α5β1) integrins, both fibronectin receptors [78]. The involvement of β1 integrin, in the anti-CD9 adhesion property, was demonstrated by blockade of β1, which abolished adhesion, as did the combined targeting of VLA-4 and VLA-5. Integrin-mediated adhesion is tightly regulated by metalloproteinases (MMP). CD9 particularly interacts with ADAM10 and ADAM17 on both leukocytes and endothelial cells, inhibiting their sheddase activity. This regulation is known to affect both soluble and membrane-bound forms of adhesion molecules, influencing adhesion dynamics [14, 79,80,81,82].
CD9 in acute leukemia
The role of CD9 in cancer development and aggressiveness remains controversial, as it may appear either as an oncogene or a tumor suppressor (Table 1). Accordingly, in clinic settings, elevated CD9 expression has been associated with improved survival in some cancer subtypes but also with poorer outcomes in others (Table 2). Indeed, its expression is often downregulated in advanced stages, and its absence is associated with poor prognosis in cancers such as lung, breast, colon, skin, ovary, uterus, stomach, oral cavity, thyroid, and prostate [46, 47, 49, 82,83,84]. However, CD9 is not universally recognized as a metastasis suppressor since, on contrary, elevated CD9 expression correlates with poorer outcomes in leukemias, certain breast and ovarian cancer subtypes, pancreatic carcinoma, and gastric carcinomas [85,86,87,88,89,90,91,92]. The role of CD9 in tumor progression likely operates through diverse mechanisms, largely influenced by its interactions with specific protein partners [93]. These multifaceted functions are intertwined across various solid tumors and hematological malignancies [25, 89].
Table 1 In vitro impact of CD9 on cancers.Table 2 CD9-related prognosis.Acute leukemias
Acute leukemias are a heterogeneous group of hematological malignancies comprising acute myeloblastic leukemia (AML) and acute lymphoblastic leukemia (ALL). In 2018, they accounted for approximately 4500 new cancer cases in France, with therapeutic responses varying widely, largely due to the intrinsic genetic complexity present at diagnosis and/or acquired during disease progression. The molecular and phenotypic characterization of acute leukemia at initial presentation is essential to design patient- and disease-specific strategies aimed at preventing relapse and improving long-term outcomes [94, 95]. Despite significant advances over the past decade, including the development of targeted therapies and immunotherapies, a substantial proportion of patients still experience relapse, sometimes several years after the completion of treatment. These relapses are mainly driven by chemoresistant clones, either pre-existing as minor subclones at diagnosis or emerging through the acquisition of secondary mutations during therapy. Relapse occurrence is influenced not only by intrinsic features of leukemic blasts but also by their microenvironment within the BM or extramedullary sites (e.g., gonads or central nervous system). Microenvironmental factors can alter leukemic cell behavior, affecting adhesion, survival, proliferation, and migration [96].
CD9 in diagnosis and prognosis
In a large cohort of pediatric acute leukemias, Leung et al. reported CD9 expression in 88.5% of B-ALL and 27.9% of T-ALL cases [97]. Multivariate analysis demonstrated that CD9 expression independently predicted poor survival outcomes and could complement established prognostic markers to enhance patient stratification. The prognostic impact of CD9 was most pronounced in the intermediate/high-risk group, particularly among patients with persistent minimal residual disease (MRD). The adverse effect of CD9 was restricted to specific cytogenetic profiles, notably BCR::ABL1-positive leukemia. In B-ALL, the ETV6::RUNX1 (ER) fusion gene is the most common genetic alteration in pediatric patients, occurring in approximately 20–25% of cases. ER-positive B-ALL is typically associated with favorable outcomes, although late relapse may occur, sometimes years after treatment completion. Studies suggest that decreased CD9 expression on lymphoblasts could predict the presence of the ER fusion and favorable prognosis in these patients [98]. Our team achieved transcriptomic analysis that revealed significantly lower CD9 expression in ER-positive B-ALL compared to other B-ALL subtypes [37, 38]. In CD9-positive ALL patients, a significantly lower 5-year relapse-free survival (RFS) rate was observed compared to CD9-negative cases [97, 99]. Although ER-positive ALL generally portends a favorable prognosis, late relapses can occur, often in sanctuary sites including BM, central nervous system (CNS), and gonads. A case report described a patient with 90% BM invasion by CD9-low blasts who relapsed 12 years later with extensive ovarian infiltration by blasts that were 90% CD9-positive, harboring the same ETV6::RUNX1 rearrangement as at diagnosis [100]. The increased CD9 expression may have altered the leukemic cell phenotype, enhancing aggressiveness and migratory capacity, possibly explaining the late relapse. In a cohort of 112 AML patients, Touzet et al. found that 40% expressed CD9 and that its expression was associated with favorable outcomes, including both the event-free survival (EFS) and RFS [56]. However, contradictory data demonstrated that CD9-positive cells exhibited higher in vitro resistance to chemotherapy and greater migratory potential compared to CD9-negative cells [57]. Moreover, according to this study, mice injected with CD9-negative AML cells survived longer than those receiving CD9-positive cells.
In acute promyelocytic leukemia (APL), a subtype of AML characterized by the t(15;17) translocation producing the PML::RARα fusion transcript, blasts typically lack expression of HLA-DR, CD11b, and CD34. In a retrospective analysis of 92 APL patients and 190 non-APL controls, Ren et al. showed that the phenotypic combination CD9+/CD11b−/HLA-DR− had 85% sensitivity and 95% specificity for APL diagnosis [101]. This is clinically significant, as differentiating APL from HLA-DR-negative non-M3 AML often requires molecular confirmation of the PML::RARα fusion, which can delay diagnosis. Notably, Satlsar et al. observed that APL cells displayed homogeneous and moderate to bright CD9 expression, whereas HLA-DR-negative non-APL patients showed more heterogeneous CD9 expression, with only 63% exhibiting moderate positivity [102]. This difference in CD9 expression patterns on leukemic blasts could thus assist clinicians in achieving more accurate and timely diagnosis. More recently, analysis of 277 APL samples identified five distinct immunophenotypic patterns of residual leukemic cells, all characterized by CD9 positivity [103]. Multiparametric flow cytometry-based MRD detection showed an 87.7% concordance rate with PML::RARα-based MRD detected by real-time quantitative polymerase chain reaction (RQ-PCR), and demonstrated excellent predictive performance for overall survival. This supports the potential use of CD9 detection as a routine clinical indicator in APL management [103, 104] (Fig. 3).
Fig. 3: CD9 expression levels in leukemia.CD9 is highly expressed in acute B and T lymphoblastic leukemias with various chromosomal rearrangements and in a more heterogeneous way in AML (Bloodspot https://www.fobinf.com/?gene=CD9&dataset=all_mile), (ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, CLL chronic lymphocytic leukemia, CML chronic myeloid leukemia, MDS myelodysplasic syndrome).
CD9 as a marker of leukemic stem cells
Nishida et al. assessed the leukemogenic potential of CD9-negative and CD9-positive sorted B-ALL cells in immune-deficient mice [105]. Mice injected with CD9-positive cells exhibited poorer survival and more rapid, extensive infiltration of hematopoietic (spleen, BM) and non-hematopoietic tissues (liver, kidneys, lungs) compared to mice receiving CD9-negative cells. Remarkably, leukemia cells isolated from spleen and BM and cultured in vitro showed that CD9-positive cells gave rise to a heterogeneous population (CD9-positive and -negative), whereas CD9-negative cells maintained low CD9 expression. Serial transplantation further demonstrated a higher engraftment potential of CD9-positive cells. These data suggest that CD9 marks leukemic stem cells (LSCs) in B-ALL and may contribute to leukemia establishment and progression [105,106,107].
Similarly, in AML, cell sorting based on CD9 expression revealed that higher CD9 expression correlated with increased engraftment ability and growth promotion in immune-deficient mice [57]. Interestingly, CD9 expression was comparable between LSCs and blasts but absent on HSCs [56, 57, 104]. Given that most LSC-associated antigens are co-expressed on normal HSCs and progenitors [108], CD9 emerges as a highly specific LSC marker, making it a relevant candidate for MRD monitoring in AML [56, 57]. Transcriptomic comparison of CD9-positive vs. CD9-negative cells revealed that alpha-2-macroglobulin (A2M) plays a key role in regulating stemness features of CD9-positive cells, sustaining their migratory capacity and resistance to cytarabine (ara-C) [57].
CD9 promotes blast migration
The role of CD9 in cancer cell proliferation, invasion, and survival appears variable and may even be opposite depending on cancer type [109,110,111]. Blocking CD9 in B-ALL cells, through anti-CD9 monoclonal antibody (mAb) or RNA interference, significantly reduced leukemic cell proliferation and increased survival of immune-deficient mice injected with leukemic cells compared to controls [107]. This was accompanied by altered expression and tyrosine phosphorylation of Src proteins, which regulate processes such as proliferation, motility, and adhesion. CD9 knockdown markedly decreased phosphorylation of PI3K (p-PI3K) and AKT (p-AKT) in B-ALL cells relative to wild-type cells, suggesting that, like other tetraspanins, CD9 can activate PI3K/AKT signaling pathway, thereby contributing to adhesion, migration, and invasion [112]. This pathway is well known to promote tumor cell adhesion, migration, and invasion by upregulating downstream effectors such as MMP2 and phosphorylated focal adhesion kinase (p-FAK) [113]. Moreover, PI3K/AKT signaling regulates apoptosis through downstream cell cycle- and apoptosis-related effectors including p53, p21, and cleaved caspase-3 [114]. Expectedly, CD9 silencing upregulated p53, p21, and cleaved caspase-3, resulting in cell cycle arrest and apoptosis induction [115]. These findings support a role for CD9 as an aggressiveness factor in B-ALL, influencing survival and invasive potential.
However, CD9 function in migration has been reported as both pro- and anti-migratory depending on the study and cell type [34, 84, 116,117,118]. This discrepancy may reflect the presence or absence of molecular partners and interactions within the tumor microenvironment. For example, ectopic expression of CD9 in the poorly motile Raji B cell line, which lacks CD9, increased in vitro migration through fibronectin- and laminin-coated filters [119]. It is plausible that cells with high CD9 levels invade the surrounding microenvironment in BM and extravasate via blood and lymphatic vessels, contributing to leukemia aggressiveness [86]. Actin cytoskeleton remodeling is crucial in cell motility, invasion, and metastasis, and CD9 modulates actin polymerization. Our team demonstrated that CD9 participates in B-ALL cell migration in response to CXCL12 via the Rac1 signaling pathway, leading to actin polymerization and cytoplasmic protrusion formation [86]. Testis-conditioned medium also promotes migration of pre-B ALL cells, possibly via CXCL12 secretion, which could explain why testis is a frequent extramedullary relapse site in pediatric ALL (3.5–8% of cases) [86, 96, 120]. CXCL12-induced migration was inhibited by an anti-CD9 mAbs, supporting the role of CD9 in extramedullary invasiveness. CD9 is known to promote migration via activation of the p38/mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinases (JNK) pathways, increasing expression of MMP2 and MMP9 [120, 121]. MMP2 degrades the ECM surrounding endothelial cells, facilitating transendothelial migration. Furthermore, simultaneous knockdown of CD9, CD81, and TSPAN12 markedly impaired membrane type-1 MMP (MT1-MMP) function, including fibronectin proteolysis, invasion, 3D (fibrin and collagen gels) growth, and MMP2 activation [122]. These tetraspanins co-immunoprecipitate and colocalize with MT1-MMP. While they do not directly affect MT1-MMP biosynthesis, they protect newly synthesized protein from lysosomal degradation and facilitate its trafficking to the cell surface. Disrupting interaction of MT1-MMP with tetraspanins may represent a therapeutic avenue to limit cancer invasion and metastasis.
CD9 expression is associated with chemoresistance in ALL
CD9 expression correlates with a chemoresistant phenotype in B-ALL by increasing protein levels of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) via PI3K pathway activation [112]. Combining an anti-CD9 antibody with classical cytotoxic drugs (vincristine, dexamethasone, or L-asparaginase) led to greater B-ALL growth inhibition and higher apoptosis beyond either treatment alone, suggesting that CD9 downregulation may be used to sensitize to chemotherapeutic agents [123]. However, the same group later demonstrated that CD9 knockout rendered B-ALL cells resistant to prednisone and dexamethasone, with restored sensitivity upon CD9 overexpression. These authors also reported that CD9 physically interacts with the glucocorticoid receptor (NR3C1) within TEMs. Although CD9 did not affect NR3C1 expression, phosphorylation, or nuclear translocation, it potentiated induction of glucocorticoid-responsive genes in resistant cells [124]. Another study assessing Ph-positive ALL cells with CD9 knockdown showed increased susceptibility to vincristine, daunorubicin, cyclophosphamide, dexamethasone, and imatinib of the SUP-B15 cell model [115]. These findings highlight a complex, context-dependent role of CD9 in drug response regulation, which could be influenced by cell-specific factors and tumor microenvironment.
Targeting CD9 in cancer
Anti-CD9 blocking antibody approaches and their limits
Therapeutic targeting of CD9 is likely to be relevant only in cancer subtypes where its expression is associated with poor prognosis, suggesting an oncogene-like behavior. In preclinical studies, the most direct approach to target a membrane protein has traditionally been the development of blocking antibodies, which have yielded robust results. As previously mentioned, CD9 is expressed in 60–80% of B-ALLs and correlates with adverse prognosis in independent studies, highlighting its potential as a therapeutic target [97]. Consequently, antibody-mediated CD9 blockade in mice xenografted with human B lymphoblasts efficiently enhanced chemosensitivity and markedly reduced leukemic homing and burden [123]. Similarly, in solid tumors, administration of the ALB6 anti-CD9 antibody in mice engrafted with human gastric cancer cells effectively inhibited tumor progression, mainly through antiproliferative, pro-apoptotic, and anti-angiogenic mechanisms [125, 126]. However, clinical development of CD9-targeting antibodies, such as the ALB6 clone, has been hindered by CD9’s role in platelet aggregation [61, 127].
A promising human antibody, AT1412 (also referred to as KBA1412), was isolated from B cells of a patient cured of stage IV metastatic melanoma [128]. This antibody targets a unique CD9 epitope distinct from those recognized by mouse antibodies. AT1412 bounds the majority of B-ALL samples but not T-ALL, and triggers antibody-dependent cellular cytotoxicity (ADCC) against CD9-positive B-ALL primary cells, with cytotoxicity correlating with binding levels. In humanized immune-deficient mice, AT1412 induced strong dose-dependent tumor rejection of B-ALL, particularly at extramedullary sites. To support clinical development, pre-clinical safety of AT1412 has been evaluated in cynomolgus monkeys [129, 130]. Data showed an 8.5-day half-life compatible with 2–3 weekly administrations, no induction of platelet aggregation or thrombosis in vitro or in vivo (intravenous administration) at therapeutic doses, and only transient thrombocytopenia with accelerated recovery in animals developing anti-AT1412 antibodies. No adverse effects on coagulation, bruising, or bleeding were observed. A first-in-human clinical trial (NCT05501821) was initiated in 2022 to evaluate AT1412 given as monotherapy or in combination with pembrolizumab in adults with advanced solid malignant tumors, and further B-ALLs [131]. So far, this study appears to demonstrate a favorable safety profile in humans, although available data remain limited to brief reports. Given CD9’s involvement in leukemia cell migration, especially in extramedullary niches, we consider the use of anti-CD9 antibodies not only as the frontline treatment but also as an adjuvant strategy to prevent relapse, in combination with standard maintenance therapy.
Since the central role of CD9 in orchestrating the transendothelial migration, effects observed after antibody treatment may not be solely due to direct CD9 inhibition. In gastric cancer cells, CD9 physically and functionally associates with epidermal growth factor receptor (EGFR) and β1 integrin [132], and each partner regulates the other. Following CD9 antibody binding, CD9 and EGFR localization changed on the cell surface, enhancing their association and accelerating EGFR internalization, thereby downregulating EGF signaling [133]. In this context, the effects observed following anti-CD9 treatment may be mediated, at least in part, by downregulation of the EGFR signaling pathway.
From a therapeutic perspective, CD9 represents a promising tumor antigen target; however, several limitations must be considered. First, its broad expression across numerous normal tissues raises concerns regarding off-target effects. Consequently, the use of CD9-targeting mAbs conjugated to toxins or cytotoxic agents carries significant risks of adverse effects [25]. To address this limitation, intratumoral injection of anti-CD9 antibodies may represent an alternative strategy to explore in solid tumors to limit systemic toxicity [134]. Second, the therapeutic implementation of direct CD9 targeting is complicated by its presence in exosomes, which may sequester and neutralize therapeutic antibodies or potentiate their pro-metastatic activity by promoting endocytosis [89]. However, conversely, an anti-CD9 Fab antibody has been shown to inhibit the EVs exchange between colon cancer cells by preventing their internalization, thereby inhibiting the phenotypic transformation observed after EVs exposure [135]. Furthermore, the clinical efficacy of tetraspanin-targeted therapies such as those directed against CD9 may be limited by factors including antibody size, susceptibility to degradation, potential side effects, and the emergence of resistance mechanisms.
Alternative to antibody approaches
Small peptides or short amino acid chains exhibiting strong binding affinity, high stability, low cytotoxicity, and favorable pharmacokinetics can be engineered for therapeutic applications. Recently, Suwatthanarak et al. investigated the suppressive effects of an 8-mer CD9-binding peptide (CD9-BP) on cancer metastasis and elucidated its mechanisms of action [136]. They demonstrated that CD9-BP inhibited melanoma cell migration and invasion in vitro. Moreover, CD9-BP reduced cancer cell metastasis by impairing exosome secretion and uptake in a triple-negative human breast cancer cell line. CD9-BP administration significantly reduced lung metastasis in a mouse model. These findings underscore the potential of CD9-targeting peptides as an alternative therapeutic strategy in metastatic cancers, as well as acute leukemia.
In the same vein, we propose that nucleic acid-based therapeutic approaches could also be considered, such as antisense oligonucleotides (ASOs) designed to target CD9 mRNA. These molecules are short, chemically modified RNA/DNA hybrids, typically 12–25 nucleotides in length, designed to specifically recognize a complementary RNA sequence and either induce its degradation or block its translation [137]. This approach has demonstrated efficacy in genetic disorders, and its potential in cancer is currently under intense investigation [138]. Such strategies may enable selective downregulation of CD9 in malignant cells, potentially overcoming some limitations associated with antibody-based therapies; however, challenges related to delivery, stability, and off-target effects remain to be addressed. Unlike antibody-based strategies that indiscriminately target all CD9-expressing cells, the delivery of small peptides and ASOs offers the possibility of achieving greater specificity [139]. This could be accomplished by coupling peptides or RNA to antibodies selectively expressed on cancer cells, for example, CD19 or CD20 in B-ALL, thereby restricting the therapeutic effect to malignant populations while sparing normal tissues [140]. Alternatively, vesicle-based delivery systems represent another promising way, as they can be engineered to transport peptides or therapeutic cargos directly to the tumor microenvironment [139, 141,142,143,144]. Such approaches may overcome the limitations of systemic CD9-targeting antibodies and reduce off-target toxicity, while harnessing CD9-related pathways for therapeutic benefit.
Discussion and perspectives
CD9 is a reliable diagnostic biomarker, whose clinical application could refine prognosis and enable MRD monitoring in several cancers to anticipate relapse (Table 2). Its dual role as either an oncogene or a tumor suppressor, however, remains debated (Table 1). In leukemia, genetic abnormalities remain the cornerstone of diagnosis and prognosis and must be systematically assessed within a short timeframe prior to risk-group assignment and treatment decisions. Yet, such analyses are not universally available, particularly in resource-limited settings. In this context, low surface expression of CD9 may serve as a robust and validated predictor of the ETV6::RUNX1 B-ALL subtype, offering a more accessible alternative to molecular testing and reducing both time and cost [38, 39]. Importantly, CD9 should be considered as a practical screening marker that can guide genetic testing rather than replace it entirely. Patients with low CD9 expression can first be screened for ETV6::RUNX1, with subsequent molecular testing restricted to those negative for this rearrangement. This approach requires refinement by precisely characterizing CD9 expression not only across ALL subtypes (Ph+, Ph-like, MLL-r/KMT2A, ETV6::RUNX1, etc.), but also disease stage (diagnosis, MRD, relapse), and anatomical sites (BM vs peripheral blood vs CNS vs gonads), ideally through larger flow cytometry/immunohistochemistry cohorts, standardized anti-CD9 antibodies, and integrative transcriptomic meta-analyses at bulk and single cell levels. In AML, CD9 expression patterns in subtype-specific (e.g., NPM1, FLT3) need to be more systematically addressed. CD9 is expressed on the most immature phenotypic AML cells but largely absent from normal hematopoietic counterparts, making it a potentially valuable tool for MRD assessment, especially in patients for whom molecular MRD markers often lack. Moreover, longitudinal data on CD9 expression dynamics under chemotherapy, immunotherapy, targeted agents, epigenetic drugs are almost absent. It remains unclear whether CD9 functions as an independent prognostic marker for relapse and MRD, or simply correlates with other risk features. As for ALLs, broader datasets and integration of CD9 into multivariate prognostic models will be required to resolve this issue.
A growing body of evidence highlights the involvement of CD9 in diverse physiological and pathological processes. However, a more comprehensive understanding of the regulatory pathways governing CD9 expression, together its functional role in LSC biology and therapy resistance, will be critical to determine whether CD9 should remain restricted to a biomarker role or could eventually be developed as a therapeutic target. As a marker, CD9 also provides the opportunity to isolate and compare the transcriptomes of CD9-positive and CD9-negative cells, thereby uncovering mechanisms associated with tumor aggressiveness as well as potential vulnerabilities. In addition, the complex interactions of CD9 within TEMs, which regulate cell adhesion to the extracellular matrix and cell migration, warrant deeper investigation given the established importance of the tumor microenvironment in cancer progression. In leukemia, the tetraspanin web and CD9 interaction partners (integrins, MMP, and signaling adaptors) are poorly characterized. Elucidating the molecular complexes and downstream pathways mediating CD9 function (e.g., PI3K, SRC, and integrin signaling) will be essential. In parallel, it also remains unclear how CD9 expression may influence sensitivity to antibody-based therapies (e.g., blinatumomab), CAR-T cells, or targeted agents. Whether CD9 contributes to immune escape, through effects on adhesion, immunological synapse formation, or antigen presentation, or instead protects LSCs from cytotoxic damage remains to be determined.
It remains difficult to draw conclusions regarding the therapeutic targeting of CD9 in humans. Like other tetraspanins, CD9 lacks intrinsic signaling capacity and instead acts as structural organizers through interactions with various partners within TEMs [17]. This property makes it challenging to disrupt its function with small inhibitory molecules, unlike membrane receptors. Nevertheless, a deeper understanding of the deregulated signaling pathways driving CD9 expression and activity across cancer subtypes may ultimately reveal upstream druggable vulnerabilities, opening new ways for selective therapeutic interventions. In leukemia, aberrant histone modifications sustain proliferation, block differentiation, and promote persistence of LSCs. Pharmacological inhibition of histone-modifying enzymes with HDAC inhibitors (vorinostat, panobinostat), the EZH2 inhibitor tazemetostat, and DOT1L inhibitors currently in clinical evaluation, offers therapeutic potential, although their effects remain broad and non-specific. Given that CD9 expression is sensitive to histone modifier inhibitors [34], it will be important to evaluate how CD9 expression evolves in treated patients. The causal mechanisms controlling CD9 transcription are incompletely defined and may involve histone modifications, as well as enhancer/promoter status, transcription factor activity, and non-coding RNAs. Addressing these gaps through chromatin mapping at the CD9 locus (ChIP-seq, ATAC-seq) combined with transcriptomic profiling at both bulk and single-cell levels will be helpful to envisage indirect modulation via, for example, epigenetic drugs capable of down- or up-regulating CD9. By contrast, strategies that directly target CD9 are still preliminary but promising. To date, the most advanced approach has relied on mAbs. But, only one clinical trial is ongoing in solid tumors, with results eagerly awaited (NCT05501821). Preclinical studies, however, report encouraging efficacy and safety data. Because CD9 is not exclusively expressed on tumor cells, but also on many healthy cells, the development of targeted therapies, particularly mAbs, remains challenging. Beyond conventional antibodies, alternative approaches deserve further investigation, including nanobodies, antibody-drug conjugates, bispecific antibodies, and CD9-directed CAR-T or NK cells. Future efforts should focus on developing high-affinity antibodies, assessing efficacy in patient-derived xenograft models, and evaluating combination strategies such as CD9 targeting together with standard chemo or immunotherapy, while also quantifying on-target/off-tumor expression to anticipate potential toxicity of these approaches on normal cells.
Conclusion
In summary, we are convinced that CD9 emerges as a compelling prognostic and biological marker in leukemia, likely reflecting LSC-associated profile, and provides a useful entry point to investigate mechanisms of resistance and relapse. Nevertheless, current evidence remains insufficient to establish whether CD9 can be translated into a durable therapeutic target in cancer. We believe that future work should systematically define CD9 expression across leukemia subtypes and during treatment stages, clarify the epigenetic mechanisms regulating its expression, and determine its causal role in LSC’s function and therapy resistance.
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Funding
This work was supported by Ligue Nationale contre le Cancer and CD Grand Ouest (VG), FHU CAMIn (EC and JRG), Enfant Cancer Santé (FM), Ministère de la l’Enseignement supérieure et de la recherche (OG), Région Bretagne ARED (EC and JRG), Manche Leucémie (EC), La Vannetaise (EC).
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These authors contributed equally: Océane Guého, Elie Cousin.
Authors and Affiliations
Univ Rennes, CNRS IGDR (Institut de Génétique et Développement de Rennes) - UMR 6290, INSERM ERL U1305, Rennes, France
Océane Guého, Elie Cousin, Anne-Gaëlle Rio, Sébastien Corre, Virginie Gandemer & Frédéric Mazurier
University Hospital, Caen, Department of Pediatric Oncology and Hematology, CHU Caen Normandie, Caen, France
Jérémie Rouger-Gaudichon
Pediatric Hematology Department, University Hospital, Rennes, France
Virginie Gandemer
Authors
- Océane Guého
- Elie Cousin
- Jérémie Rouger-Gaudichon
- Anne-Gaëlle Rio
- Sébastien Corre
- Virginie Gandemer
- Frédéric Mazurier
Contributions
OG, EC, and FM contribute to manuscript conceptualization, writing, editing, and reviewing. JRG, AGR, SC, and VG contribute to editing and reviewing.
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Correspondence to Virginie Gandemer or Frédéric Mazurier.
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Guého, O., Cousin, E., Rouger-Gaudichon, J. et al. CD9, a tetraspanin in cancer: biology and therapeutic promise in acute leukemia. Oncogenesis 14, 47 (2025). https://doi.org/10.1038/s41389-025-00590-1
Received: 25 July 2025
Revised: 17 October 2025
Accepted: 24 October 2025
Published: 05 December 2025
Version of record: 05 December 2025
DOI: https://doi.org/10.1038/s41389-025-00590-1