5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) has been one of the most commonly used pharmacological modulators of AMPK activity. The majority of early studies on the role of AMPK, both in the physiological regulation of metabolism and in cancer pathogenesis, were based solely on the use of AICAr as an AMPK-activator. Even with more complex models of AMPK downregulation and knockout being introduced, AICAr remained a regular starting point for many studies focusing on AMPK biology. However, there is an increasing number of studies showing that numerous AICAr effects, previously attributed to AMPK activation, are in fact AMPK-independent. This review aims to give an overview of the present knowledge on AMPK-dependent and AMPK-independent effects of AICAr on metabolism, hypoxia, exercise, nucleotide synthesis, and cancer, calling for caution in the interpretation of AICAr-based studies in the context of understanding AMPK signaling pathway.

Bendamustine is an alkylating agent classified into the group of nitrogen mustard analogues, synthesized almost sixty years ago. It was registered in former East Germany in 1971 and approved by the US Food and Drug Administration in 2008 for treatment of chronic lymphocytic leukemia and indolent B‑cell non‑Hodgkin lymphoma. Considering its beneficial properties in the therapy of relapsed or refractory hematological malignancies, synergistic effects with other antineoplastic agents and increasing recent reports on its immunomodulatory effects, bendamustine has once again gained its justified attention. The uniqueness of bendamustine‑mediated effects should be observed keeping in mind its distinctive structure with structural similarities to both alkylating agents and purine analogs. In the present review, the current knowledge on the use of bendamustine in oncology, its pharmacokinetics, mechanism of action and toxicity was summarized. In addition, its immune‑modulating effects that have not been fully elucidated so far are emphasized, hoping to encourage further investigations of this unique drug.

This study is the first to demonstrate that human stromal cell lines and primary mesenchymal stromal cells from patients enhance the in vitro differentiation of acute myeloid leukemia (AML) cells induced by pyrimidine synthesis inhibitors, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), and brequinar. Furthermore, this is the first report to show that AICAr affects mouse bone marrow stromal cells by activating AMP-activated protein kinase (AMPK) and that human stromal cells are superior to mouse cells for testing the effects of drugs on AML differentiation.

Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress–driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine–purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.

Background: B-cell malignancies comprise a biologically diverse group of neoplasms, with only rare reports describing the co-occurrence of two distinct lymphoid entities. While concurrent presentation of mature B-cell neoplasms has been documented, the simultaneous occurrence of B-cell acute lymphoblastic leukemia (B-ALL) and plasma cell neoplasm (PCN) has previously been reported rarely. Such cases may provide insight into the clonal architecture and evolutionary pathways underlying lymphoid malignancies. Case presentation: We report a 76-year-old man presenting with cytopenias and leukocytosis, in whom initial bone marrow evaluation and immunophenotyping established a diagnosis of B-ALL with a pre-B phenotype. At the time of diagnosis, flow cytometry also identified a distinct population of aberrant plasma cells, raising the possibility of a concurrent plasma cell neoplasm. Follow-up bone marrow analysis confirmed the coexistence of two immunophenotypically and morphologically distinct malignant populations: immature lymphoblasts consistent with B-ALL and clonal plasma cells. Initial ALL-directed therapy induced remission of both components. However, subsequent disease evolution demonstrated a clear phenotypic shift, with relapse characterized by expansion of a plasmablastic/plasma cell population consistent with PCN, while the B-ALL component remained undetectable by minimal residual disease assessment. Treatment was therefore redirected toward a myeloma-based regimen, which was limited by toxicity and failed to achieve disease control. Genomic analysis supported the presence of two clonally related but distinct malignancies. Conclusion: These findings support a model of early clonal divergence from a common progenitor rather than independent malignancies or linear differentiation. This case highlights the complexity of clonal evolution in B-cell malignancies and underscores the importance of integrated genomic and immunophenotypic analysis in understanding disease biology.

Background Immune-mediated diseases affect a substantial proportion of the population and are characterised by overlapping pathogenic mechanisms that extend across traditional specialty boundaries. Their management increasingly requires coordinated multidisciplinary approaches capable of integrating expertise from multiple medical disciplines. Objective This article examines the rationale for integrated care in immune-mediated diseases and discusses the emerging role of the UEMS Multidisciplinary Joint Committee (MJC) on Immune-Mediated Diseases as a European platform for collaboration, education, and professional coordination. Discussion Immune-mediated diseases frequently involve multiple organ systems and shared inflammatory pathways, creating challenges for conventional organ-based models of care. Multidisciplinary approaches have demonstrated benefits regarding clinical outcomes, patient experience, and coordination of care. Within this context, the UEMS MJC on Immune-Mediated Diseases provides an organisational structure supporting dialogue and cooperation across specialties involved in the diagnosis and management of these conditions. Following the election of a new Bureau in January 2026, the Committee has entered a new phase focused on strengthening multidisciplinary collaboration, expanding visibility within UEMS, and developing practical initiatives in education, competency development, and clinical harmonisation. Conclusions The UEMS MJC on Immune-Mediated Diseases represents an important step toward more integrated and coordinated management of immune-mediated diseases within European specialist medicine. By fostering sustained multidisciplinary collaboration and focusing on realistic educational and professional objectives, the Committee has the potential to strengthen coherence across specialties and contribute to improved patient care throughout Europe.