In a groundbreaking advance in the fight against acute myelogenous leukemia (AML), a collaborative study spearheaded by researchers from Ludwig Cancer Research has illuminated a promising new therapeutic strategy that could revolutionize treatment paradigms for this aggressive blood cancer. Despite medical advances, AML remains a formidable adversary, with median survival after diagnosis languishing at a mere 8.5 months. The latest findings, now published in Nature, chart a course toward enhancing patient outcomes by targeting the fundamental biological processes that give rise to the malignancy’s persistence.
One of AML’s defining features is a pervasive block in the differentiation of myeloid progenitor cells within the bone marrow. This obstruction arrests the maturation of these cells, resulting in the accumulation of immature precursors that flood the marrow and peripheral blood. This paralyses normal hematopoiesis—the vital process governing the generation and renewal of blood cells—undermining not just immune competence but a multitude of physiological functions reliant on healthy blood cell populations. Recognizing this differentiation blockade as a keystone of AML pathology has long inspired researchers to explore therapeutic avenues that could dismantle this barrier.
Led by Professor Yang Shi of Ludwig Oxford and Dr. Amir Hosseini, with pivotal contributions from Abhinav Dhall at Harvard Medical School, and collaborators at the University of Pennsylvania and University of Helsinki, the study introduces a novel combination drug therapy that tackles AML at this very checkpoint. Their work hinges on a dual mechanism designed to simultaneously activate gene expression programs that promote cellular differentiation while actively repressing those that fuel unchecked proliferation and tumorigenesis. This two-pronged approach is meticulously crafted to coax leukemic cells out of their arrested developmental state and curb their malignant growth kinetics.
Historically, the concept of differentiation therapy in AML is not new. Acute promyelocytic leukemia (APL), a distinct AML subtype, has been effectively treated with differentiation agents such as all-trans retinoic acid combined with arsenic trioxide, achieving cure rates near 95%. However, this success has been largely restricted to APL, leaving a vast majority of AML patients without analogous effective differentiation-based treatments. Addressing this unmet need, Shi and his colleagues have turned their focus to epigenetic regulators—enzymes that modulate gene expression without altering the underlying DNA sequence—specifically targeting key drivers of the differentiation blockade.
Central to the researchers’ strategy is LSD1 (lysine-specific demethylase 1), an enzyme first identified by Shi’s laboratory in 2004. LSD1 functions as an epigenetic eraser, removing methyl groups from histone proteins around which DNA is tightly coiled, thereby influencing the accessibility of genes to the cellular machinery that transcribes them. In AML cells, heightened LSD1 activity contributes to the maintenance of leukemic stem cells by reinforcing the gene expression landscape that enforces their immature, undifferentiated state. While LSD1 inhibitors have shown potential in inducing differentiation, their clinical application has been hampered by high toxicity when administered as monotherapies.
To overcome this, the study employed a systematic screen using mouse leukemic cells to identify drugs that could synergize with LSD1 inhibitors, ultimately spotlighting a clinically evaluated GSK3α/β inhibitor as a potent partner. Glycogen synthase kinase 3 (GSK3) is an enzyme known to participate in a litany of cellular processes, including WNT signaling—a pathway frequently hijacked in cancers including AML, promoting stemness and proliferation. Combining low-dose LSD1 inhibition with GSK3 blockade proved to be a potent formula for inducing differentiation and halting proliferation across multiple AML subtypes in vitro.
Subsequent in vivo experiments provided further encouragement. When administered to mice engrafted with human AML cells, the combination therapy not only promoted leukemic cell maturation and suppressed their division but also extended the survival of these animal models. Intriguingly, the therapeutic effects appeared to selectively target leukemic cells without adversely affecting normal hematopoietic stem cells, suggesting a favorable therapeutic index that could translate into lower toxicity profiles for patients.
The molecular analyses underpinning these findings revealed that the drug combination reprograms gene expression networks by suppressing the stemness signature that confers malignancy, while promoting differentiation pathways. This molecular rewiring mitigates the pathological overactivation of the WNT signaling cascade—an insight that may have far-reaching implications beyond AML, potentially informing treatment strategies for other malignancies marked by similar pathway dysregulations.
Moreover, gene-expression profiling of AML patients demonstrated that the therapeutic signature induced by the drug combo aligns with the expression landscape observed in individuals exhibiting prolonged survival. This correlation underscores the potential real-world relevance of the preclinical findings and bolsters the rationale for advancing this treatment regimen into clinical trials. Both LSD1 and GSK3α/β inhibitors are already under clinical evaluation for other indications, smoothing the pathway for translational research and swift clinical implementation.
The team’s holistic approach blends innovative epigenetic modulation with an existing pharmacological arsenal to surmount a longstanding hurdle in AML therapy. By dismantling the differentiation blockade, their combination therapy holds promise not only for extending survival but also for improving the quality of life in AML patients, who often endure toxic and debilitating treatments. The prospect of converting a lethal, rapidly progressing cancer into a manageable or even curable disease marks a new frontier in oncology.
Looking ahead, the investigators are poised to translate these promising preclinical results into human clinical trials, where safety and efficacy will be rigorously tested. Their work exemplifies the power of integrative science—melding molecular biology, pharmacology, and clinical insight—to produce breakthrough therapies. If successful, this approach could redefine AML treatment standards and inspire analogous strategies against other epigenetically driven cancers.
This landmark study was made possible through generous support from Ludwig Cancer Research, the U.S. National Institutes of Health, the Research Council of Finland, Cancer Foundation Finland, the Sigrid Jusélius Foundation, the National Institute for Health Research, the Oxford Biomedical Research Centre, and Cancer Research UK. Harnessing the synergy of international expertise and funding, it represents a collective stride forward in the global battle against cancer.
In addition to his leadership role at Ludwig Oxford, Yang Shi serves as a Professor in the Nuffield Department of Medicine at the University of Oxford, further underscoring the study’s strong academic foundation. The collaborative, interdisciplinary nature of this research embodies the future of cancer therapeutics, where innovative ideas swiftly transition from bench to bedside, offering renewed hope to patients facing devastating diagnoses.
Subject of Research: Therapeutic strategies targeting differentiation blockade in acute myelogenous leukemia (AML)
Article Title: Not provided
News Publication Date: April 16, 2025
Web References:
https://www.nature.com/articles/s41586-025-08915-1
References: Information not explicitly provided beyond the publication in Nature.
Image Credits: Not provided
Keywords: Health and medicine, Cancer research, Cancer, Genomics
