Biased signaling, also known as functional selectivity of receptors, describes a phenomenon where the same receptor can elicit different effects in a cell depending on which ligand binds to it. In other words, various ligands can activate different signaling pathways in the cell, leading to diverse cellular responses. More than one different ligand can bind to the same receptor simultaneously. This process is known as receptor coactivation. When two ligands bind to the receptor simultaneously, they can interact with each other or with other intracellular molecules, resulting in different outcomes compared to the situation where only one ligand is present (Fig. 1). This mechanism allows cells to regulate their responses to environmental signals in complex physiological conditions.

In AML, hematopoiesis, the process of blood cell formation, is profoundly disrupted by genetic mutations and dysregulated signaling pathways that drive the expansion of leukemic stem cells (LSCs). This process requires a tightly regulated balance between stem cell differentiation and self-renewal, but mutations in key hematopoietic regulatory genes disrupt this equilibrium. Mutations in FLT3, NPM1, and DNMT3A, critical for normal hematopoiesis, result in unchecked proliferation of progenitor cells and prevent their differentiation into mature blood cells. Consequently, immature leukemic blasts accumulate, suppressing normal hematopoiesis. Further compounding these disruptions, alterations in transcription factors such as RUNX1 or CEBPA block myeloid differentiation and enhance LSC self-renewal. These changes not only sustain the survival and expansion of LSCs but also contribute to their resistance to conventional therapies, often driving disease relapse (Khwaja et al., 2016).

Aberrations in AML manifest as lineage-specific disruptions, including impaired myeloid maturation in subtypes like M1 and M2, monocytic hyperproliferation in M5, and erythroid lineage dominance in M6. These lineage-specific defects are driven by biased signaling pathways that selectively activate or amplify specific molecular circuits. Dysregulation of JAK-STAT and Wnt/β-catenin pathways hinders differentiation in early myeloid lineages, while hyperactivation of nuclear factor-κB (NF-κB) and MAPK pathways promotes proliferation and survival in monocytic subtypes. Similarly, mutations in transcription factors like RUNX1 or fusion proteins such as PML-RARA impose differentiation arrest by reprogramming signaling networks. This biased signaling framework presents both challenges and opportunities for therapeutic intervention. Targeted therapies aim to exploit these aberrant pathways to selectively eliminate leukemic cells while preserving normal hematopoiesis. For example, FLT3 inhibitors target receptor-driven dysregulation, while menin-MLL inhibitors address transcriptional dysregulation. These approaches are under active investigation across AML subtypes (Table 1).

The existence of biased signaling holds profound implications for drug discovery and development. Conventional drug development primarily sought ligands that uniformly activate or inhibit receptors. However, comprehending biased signaling allows researchers to design drugs that precisely target desired pathways, potentially mitigating side effects and enhancing therapeutic efficacy. Biased signaling phenomena have been observed across diverse receptor systems, encompassing G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs), and nuclear hormone receptors. Numerous GPCRs play crucial roles in cell proliferation and survival and may exhibit abnormal expression in cancer cells. For example, the chemokine receptor CXCR4 plays a significant role in tumor metastasis and angiogenesis (Maiga et al., 2016). However, in AML, biased signaling interacts with critical cellular pathways, such as those regulating cell proliferation, apoptosis, and survival, which are frequently dysregulated due to genetic mutations and cellular heterogeneity. For instance, the chemokine receptor CXCR4, highly expressed in many AML subtypes, influences the PI3K-Akt and MAPK pathways, which are pivotal for leukemic cell migration, survival, and resistance to therapy, through G-protein- and β-arrestin-mediated pathways. While, RTKs such as FLT3 and c-KIT drive AML cell proliferation via biased activation of downstream kinases like MAPK and PI3K. Both receptor types leverage biased signaling to engage specific intracellular pathways, with GPCRs offering versatility in signaling outputs and RTKs facilitating direct links to growth and survival pathways. But, the selectivity of biased signaling arises not only from the ligand-receptor interaction but also from the conformational changes induced in the receptor upon binding, which may vary across AML subtypes depending on mutations such as FLT3-ITD or NPM1, altering their downstream effects and drug sensitivity (Monfared et al., 2021).

Leveraging biased signaling enables the development of drugs with more precise therapeutic effects. It can regulate various physiological processes, including blood pressure, heart rate, digestion, hormone secretion, cell growth, migration, vision, and olfaction. For example, a drug targeting a GPCR involved in heart failure could be used to activate pathways that enhance cardiac contractility while avoiding those associated with adverse effects such as arrhythmias (Thai et al., 2024). Despite its potential, integrating biased signaling into drug development may pose a challenge and several obstacles must be addressed to harness its benefits effectively. The complexity of ligand-receptor interactions, influenced by ligand-induced conformational changes, presents challenges in predicting therapeutic outcomes. AML genetic and cellular heterogeneity further complicates the identification of effective biased ligands, as responses may vary across subpopulations. Off-target effects, a persistent issue, risk activating unintended pathways, leading to toxicity. Additionally, the dysregulated signaling pathways driving AML progression are not fully understood, limiting the ability to design precise interventions. Therapeutic resistance, often mediated by adaptive signaling mechanisms, and the lack of biomarkers to predict patient responses also hinder the application of biased signaling. To overcome these challenges, integrating computational modeling, high-throughput screening, single-cell multi-omics, and advanced drug delivery systems is essential. Studies on receptor trafficking, ligand specificity, and the tumor microenvironment, alongside biomarker discovery, can refine therapeutic approaches and enable personalized treatment strategies for AML. Research into GPCRs such as CXCR4/CXC12 axis, known to play roles in tumor metastasis and drug resistance, offers the promise of biased signaling to improve AML therapy outcomes, offering precise and effective treatment options while minimizing side effects (Chen et al., 2020).

Overall, biased signaling represents a significant shift in our understanding of receptor pharmacology and holds promise for developing safer and more effective drugs. Continued exploration in this field has the potential to revolutionize drug discovery and reshape personalized medicine. Therefore, this review will focus on acute myeloid leukemia (AML), a type of cancer originating in the bone marrow's (BM) blood-forming cells, and potential therapeutic targets based on biased signaling receptors. AML is a highly aggressive blood cancer characterized by the rapid proliferation of abnormal myeloid cells in the BM and blood. Despite advancements in treatment, AML remains challenging to treat, necessitating the exploration of novel therapeutic approaches such as investigating the dysregulated signaling pathways contributing to disease development and progression (Bolkun et al., 2023).