MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms

Leukemia www.nature.com/leu REVIEW ARTICLE OPEN MDM2 inhibitors in myeloid cancers: from basic biology to clinical use in myeloproliferative neoplasms Haifa K. Al-Ali 1 , Sarah T. Heidel2, Francesca Palandri 3 and Florian H. Heidel 4✉ 1234567890();,: © The Author(s) 2026 Pharmacologic targeting of murine double minute 2 (MDM2) represents one of the most compelling strategies for therapeutic reactivation of wild-type p53 in hematologic malignancies. The MDM2–p53 autoregulatory loop is a central regulator of cellular stress responses, and in myeloid neoplasms—including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPN)— p53 is frequently retained but functionally suppressed through MDM2 overexpression and oncogenic signaling, notably via JAK–STAT activation. Over the past decade, successive generations of MDM2 inhibitors have translated structural and mechanistic insights into clinical investigation, yielding critical lessons regarding dosing paradigms, hematologic toxicity, biomarker-driven patient selection, and mechanisms of resistance, including TP53-mutant clonal selection. While early phase III trials in AML were negative, recent studies in myelofibrosis demonstrate clinically meaningful spleen, symptom, and molecular responses, supporting disease-modifying potential in TP53–wild-type settings. Adaptive platform designs and rational combinations with JAK inhibitors, BCL-2 antagonists, and interferons have further refined therapeutic strategies. Emerging MDM2 degraders and next-generation agents aim to overcome feedback limitations and improve therapeutic index. This review integrates mechanistic foundations, clinical development, resistance biology, and future directions, highlighting how decades of basic science have reshaped p53 reactivation into a precision therapeutic paradigm in myeloid disease. Leukemia; https://doi.org/10.1038/s41375-026-02975-6 OVERVIEW The pharmacologic targeting of murine double minute 2 (MDM2) has emerged as one of the most conceptually elegant and clinically instructive advances in modern hematologic oncology. Rooted in fundamental discoveries defining the MDM2–TP53 autoregulatory loop as a master regulator of cellular stress responses, this field has progressed from structural and biochemical insight into a clinically actionable strategy for reactivating endogenous tumor suppressor function. In myeloid malignancies —particularly myeloproliferative neoplasms (MPNs) and acute myeloid leukemia (AML)—where TP53 is frequently retained in its wild-type form but functionally restrained, MDM2 inhibition offers a unique opportunity to therapeutically exploit an intact but suppressed p53 pathway. Over the past decade, successive generations of MDM2 inhibitors have translated these principles into the clinic, yielding critical lessons regarding target biology, dosing paradigms, toxicity management, clonal evolution, and biomarker-driven patient selection. At the same time, emerging data have revealed MDM2 as a convergence point for oncogenic signaling, inflammatory cues, and cytokine-driven pathways— most notably JAK–STAT signaling in MPN—thereby positioning MDM2 inhibition not merely as a cytotoxic strategy, but as a potential disease-modifying intervention. In this review, we integrate mechanistic foundations of the MDM2–p53 axis with the evolution of MDM2 inhibitor development, summarize key clinical experiences across myeloid neoplasms, and discuss resistance mechanisms, safety considerations, and future directions, including rational combination strategies and next-generation approaches such as MDM2 degraders. Together, these insights delineate how decades of basic biology have culminated in a therapeutic paradigm that continues to reshape our understanding of p53 reactivation in myeloid disease. MECHANISTIC FOUNDATIONS: THE MDM2-TP53 AXIS IN CELLULAR HOMEOSTASIS Structural and functional architecture of MDM2 MDM2 functions as the principal negative regulator of the tumor suppressor p53 and represents a central signaling hub that integrates structural specificity, post-translational modification, and subcellular trafficking to control cellular fate decisions. The MDM2 oncoprotein is composed of several functionally specialized domains, each contributing to its regulatory versatility. The N-terminal domain harbors the p53-binding interface, which forms a deep hydrophobic cleft accommodating an amphipathic α-helix of p53. High-resolution crystallographic studies demonstrated that three conserved p53 residues—Phe19, Trp23, and Leu26—insert into this pocket, directly masking the p53 transactivation domain and thereby inhibiting transcriptional activation of downstream target genes [1, 2]. 1 University Hospital Halle (Saale), Krukenberg Cancer Center Halle, Halle, Germany. 2Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 3IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy. 4Hematology, Hemostasis, Oncology and Cell Therapy, Hannover Medical School (MHH), Hannover, Germany. ✉email: florian Received: 14 February 2026 Revised: 26 March 2026 Accepted: 20 April 2026 H.K. Al-Ali et al. 2 Fig. 1 Mechanistic function of the MDM2-p53 axis: regulation under normal conditions, cell stress, and MDM2-inhibitor treatment. Centrally, MDM2 contains an acidic domain followed by a zinc finger motif that mediates protein–protein interactions beyond p53 binding, particularly with ribosomal proteins such as L5 and L11. These interactions couple MDM2 activity to ribosomal biogenesis and nucleolar stress sensing. Cancer-associated mutations affecting zinc-coordinating cysteine residues (e.g., C305F, C308Y) disrupt ribosomal protein binding, alter MDM2 subcellular localization, and impair efficient p53 degradation, underscoring the importance of this domain in maintaining regulatory fidelity [3]. The C-terminal RING finger domain confers E3 ubiquitin ligase activity, enabling MDM2 to recruit E2 ubiquitin-conjugating enzymes and catalyze mono- and polyubiquitination of lysine residues within the p53 C-terminus, thereby targeting p53 for proteasomal degradation [4]. In addition, MDM2 possesses intrinsic nuclear localization and export signals, allowing it to function as a nuclear–cytoplasmic shuttle that escorts p53 from the nucleus to cytoplasmic proteasomes, adding a spatial layer of control to p53 suppression [5, 6] (Fig. 1). The autoregulatory feedback loop The MDM2–p53 interaction is embedded within one of the most tightly controlled autoregulatory feedback loops in mammalian cells. Under basal conditions, p53 is maintained at low steadystate levels through continuous MDM2-mediated ubiquitination and degradation. Upon cellular stress—such as DNA damage, oncogene activation, hypoxia, or inflammatory signaling—p53 becomes stabilized and transcriptionally active, inducing a broad stress response program. Among its earliest and most robust transcriptional targets is MDM2 it (...truncated)