IL3RA

Official Full Name

interleukin 3 receptor subunit alpha

Organism

Homo sapiens

GeneID

3563

Background

The protein encoded by this gene is an interleukin 3 specific subunit of a heterodimeric cytokine receptor. The receptor is comprised of a ligand specific alpha subunit and a signal transducing beta subunit shared by the receptors for interleukin 3 (IL3), colony stimulating factor 2 (CSF2/GM-CSF), and interleukin 5 (IL5). The binding of this protein to IL3 depends on the beta subunit. The beta subunit is activated by the ligand binding, and is required for the biological activities of IL3. This gene and the gene encoding the colony stimulating factor 2 receptor alpha chain (CSF2RA) form a cytokine receptor gene cluster in a X-Y pseudoautosomal region on chromosomes X or Y. Alternatively spliced transcript variants encoding distinct isoforms have been found. [provided by RefSeq, Jun 2012]

Synonyms

IL3R; CD123; IL3RX; IL3RY; IL3RAY; hIL-3Ra; IL-3R-alpha;

Bio Chemical Class

Cytokine receptor

Protein Sequence

MVLLWLTLLLIALPCLLQTKEDPNPPITNLRMKAKAQQLTWDLNRNVTDIECVKDADYSMPAVNNSYCQFGAISLCEVTNYTVRVANPPFSTWILFPENSGKPWAGAENLTCWIHDVDFLSCSWAVGPGAPADVQYDLYLNVANRRQQYECLHYKTDAQGTRIGCRFDDISRLSSGSQSSHILVRGRSAAFGIPCTDKFVVFSQIEILTPPNMTAKCNKTHSFMHWKMRSHFNRKFRYELQIQKRMQPVITEQVRDRTSFQLLNPGTYTVQIRARERVYEFLSAWSTPQRFECDQEEGANTRAWRTSLLIALGTLLALVCVFVICRRYLVMQRLFPRIPHMKDPIGDSFQNDKLVVWEAGKAGLEECLVTEVQVVQKT

Open

Disease

Acute myeloid leukaemia, Asthma, B-cell lymphoma, Follicular lymphoma, Kidney failure, Leukaemia, Low bone mass disorder, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell lymphoma, Myelodysplastic syndrome

Approved Drug

1 +

Clinical Trial Drug

24 +

Discontinued Drug

1 +

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Detailed Information

The IL3RA gene, located on Xp22.3, encodes CD123, a 70 kDa type I transmembrane glycoprotein that contains three extracellular immunoglobulin-like domains. The expression of IL3RA is tightly regulated at both transcriptional and epigenetic levels. At the transcriptional level, the EP300-ZNF384 fusion protein can directly bind to an A-rich sequence within the IL3RA promoter region, specifically at positions -222 to -234 bp, resulting in an approximate eightfold increase in gene expression in B-cell acute lymphoblastic leukemia (B-ALL). Epigenetically, IL3RA expression can be modulated by histone modifications, as treatment with histone deacetylase (HDAC) inhibitors has been shown to downregulate IL3RA, likely through reduction of H3K27ac marks, demonstrating a dual layer of regulatory control that impacts disease biology. Clinical analyses of patient samples indicate that IL3RA is positive in 41.38% of newly diagnosed B-ALL cases, whereas T-cell acute lymphoblastic leukemia (T-ALL) exhibits minimal expression. Furthermore, IL3RA expression markedly decreases during remission but is rapidly re-elevated at relapse, underscoring its potential role as a dynamic biomarker for disease progression.

Figure 1. Schematic representation of IL-3 receptor structure and its downstream signaling pathways. (Podolska MJ, et al., 2024)

Functionally, CD123, as the alpha chain of the interleukin-3 receptor, contributes to leukemogenesis and tumor progression through several interconnected mechanisms. Upon binding of IL-3, CD123 activates the JAK2/STAT5 signaling pathway, which subsequently upregulates anti-apoptotic proteins such as BCL-2 and MCL-1, thereby promoting the self-renewal and survival of leukemia stem cells (LSCs). In acute myeloid leukemia (AML) patients, the proportion of CD34⁺CD38⁻CD123⁺ cells is significantly elevated, highlighting the enrichment of this population in the leukemic stem cell compartment compared to patients in remission and healthy controls. Beyond intrinsic cellular survival, CD123 also plays a critical role in remodeling the tumor microenvironment. Surface expression of CD123 on leukemia cells mediates adhesion to mesenchymal stem cells (MSCs) via integrin α4/VCAM-1 interactions, activating downstream PI3K/AKT signaling and conferring resistance to chemotherapy. Moreover, CD123 contributes to immune evasion by promoting the secretion of immunosuppressive cytokines, including TGF-β and IL-10, which induce the expansion of myeloid-derived suppressor cells (MDSCs) and inhibit T-cell-mediated antitumor responses, collectively facilitating malignant progression and therapy resistance.

Table 1. Overview of CD123-Targeted Therapeutics

Medicine	Target	Mechanism of Action	Indications under Investigation	Development Phase	Research and Development Unit	Drug Type
Talacotuzumab	CD123	CD123 Inhibitor	Acute myeloid leukemia, Systemic lupus erythematosus	Clinical Phase 3	CSL	Monoclonal antibody
Flotetuzumab	CD123/CD3	Bispecific T-cell binder	Acute myeloid leukemia, Myelodysplastic syndromes	Clinical Phase 2	MacroGenics	Bispecific T-cell binder
SAR-440234	CD123/CD3	Bispecific T-cell binder	CD123-positive acute myeloid leukemia	Clinical Phase 2	Sanofi	Bispecific T-cell binder
Vibecotamab	CD123/CD3	Bispecific T-cell binder	Acute myeloid leukemia, Lymphocytic leukemia, Myelodysplastic syndromes	Clinical Phase 2	Xencor	Bispecific T-cell binder
Mipletamig	CD123/CD3	Bispecific T-cell binder	Acute myeloid leukemia, Myelodysplastic syndromes	Clinical Phase 1	Aptevo Therapeutics	Bispecific T-cell binder
MGD-024	CD123/CD3	Bispecific T-cell binder	CD123-positive acute myeloid leukemia	Clinical Phase 1	MacroGenics	Bispecific T-cell binder
Pivekimab Sunirine	CD123	ADC	Hematologic neoplasms, Acute myeloid leukemia, Aggressive systemic mastocytosis	Clinical Phase 2	ImmunoGen	ADC
AZD-9829	CD123	ADC	Blastic plasmacytoid dendritic cell neoplasm, CD123-positive acute myeloid leukemia, CD123-positive hematological neoplasms	Clinical Phase 1/2	AstraZeneca PLC	ADC
BAY-943	CD123	ADC	CD123-positive hematological neoplasms, CD19-positive B-cell acute lymphoblastic leukemia	Clinical Phase 1	Bayer AG	ADC

Clinically, CD123 has emerged as an actionable therapeutic target, with multiple strategies under development. Antibody-based therapies, such as Tagraxofusp, an IL-3-PE38 fusion protein, have demonstrated efficacy in blastic plasmacytoid dendritic cell neoplasm (BPDCN), achieving a five-year survival rate of 52% in Phase III trials. CAR-T cell therapies, exemplified by UCART123, have shown promising results in AML, with a complete remission rate of 45% in early-phase clinical studies, although the risk of cytokine release syndrome (CRS) requires careful management. Small-molecule inhibitors targeting downstream signaling, such as the STAT5 inhibitor Pimozide, have been shown to reduce leukemia burden by 80% in EP300-ZNF384-positive B-ALL preclinical models, highlighting the potential of combinatorial or pathway-specific approaches. The clinical utility of CD123 extends beyond direct therapeutic targeting; dynamic monitoring of CD123⁺ cells during treatment provides prognostic insights, as their proportion can rise above 15% up to three months before relapse, serving as an early indicator of disease recurrence. Furthermore, CD123 positivity has been associated with poorer treatment outcomes, including a 35% lower complete remission rate and a median overall survival shortened by 16 months compared with CD123-negative cases. Combinatorial approaches, such as co-administration of CD123 CAR-T cells with BTK inhibitors, have demonstrated the ability to overcome protective microenvironmental signals and improve progression-free survival in preclinical lymphoma models.

Despite its promise, CD123-targeted therapy faces significant challenges, primarily related to on-target off-tumor toxicity. Physiological expression of CD123 on plasmacytoid dendritic cells (pDCs) and hematopoietic stem cells (HSCs) can lead to adverse events, including thrombocytopenia and depletion of normal dendritic cell populations. Strategies to mitigate these risks include the development of switchable CAR designs, such as the iCasp9 safety switch, and dual-target CAR constructs, including CD123/CLEC12A bispecific designs, to improve specificity and safety. Another critical consideration is antigen escape, as CD123-negative clones can emerge during therapy, accounting for up to 30% of residual disease; dual-targeting or sequential therapeutic strategies may address this challenge. Importantly, precision stratification based on fusion gene status, such as EP300-ZNF384 positivity, may allow for optimal patient selection and enhance the therapeutic benefit of CD123-targeted interventions, suggesting a personalized approach that integrates molecular diagnostics with advanced immunotherapeutic strategies.

Reference

Kiss MG, Mindur JE, Yates AG, et al. Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis. Immunity. 2023 Jul 11;56(7):1502-1514.e8.
Podolska MJ, Grützmann R, Pilarsky C, et al. IL-3: key orchestrator of inflammation. Front Immunol. 2024 Jun 13;15:1411047.

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