A groundbreaking preclinical study has unveiled the potential of repurposing three clinically available drugs to target one of the most aggressive and devastating forms of childhood leukemia. This rare subtype, known as KMT2A::AFF1 positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL), primarily afflicts infants under the age of one and is notorious for its rapid progression, high relapse rates, and limited therapeutic options. The study, conducted at the University of Edinburgh and involving collaborative researchers from the Princess Máxima Center for Pediatric Oncology, provides compelling evidence that acetazolamide, tacrolimus, and LB-100—drugs currently in use or under investigation for other diseases—can suppress the leukemia’s growth in experimental animal models.
The urgency for novel therapies in infant leukemia stems from its particularly aggressive nature. KMT2A::AFF1 rearrangement drives oncogenesis through profound genetic alterations, conferring a malignancy with poor prognosis under current treatment paradigms. Existing treatment regimens largely rely on intensive chemotherapy protocols, which, while improving survival outcomes for some, are accompanied by severe toxicities that adversely affect quality of life and long-term health of these young patients. Pediatric oncologists have long faced a therapeutic dilemma: how to effectively eradicate cancer cells without imposing debilitating side effects on an already vulnerable population.
The team’s innovative approach centered on exploring the epigenetic regulation of leukemic cells mediated by microRNAs (miRNAs), small non-coding RNAs that modulate gene expression post-transcriptionally. Researchers identified three specific miRNAs—miR-194, miR-99b, and miR-125a-5p—that were consistently underexpressed in KMT2A::AFF1 positive leukemia cells. These miRNAs act as critical regulators of oncogenic pathways, and their deficiency appears to enable the cancer’s unchecked proliferation and survival. Restoration of these miRNAs in murine models markedly impaired leukemia progression, highlighting a vulnerable biological node.
Further molecular analyses pinpointed three genes downstream of these miRNAs that contribute importantly to leukemia cell viability. Targeting these genes pharmacologically could, therefore, disrupt leukemic cell maintenance. By leveraging existing pharmacological agents known to interact with these molecular targets, the researchers identified acetazolamide, tacrolimus, and LB-100 as promising candidates. Each of these drugs carries a distinct mechanism: acetazolamide acts as a carbonic anhydrase inhibitor, tacrolimus functions as an immunosuppressant modulating calcineurin activity, and LB-100 is a potent inhibitor of protein phosphatase 2A (PP2A).
In vivo experiments demonstrated that all three drugs exert potent anti-leukemic effects, significantly reducing the leukemic burden in animal models. Remarkably, acetazolamide displayed the most favorable therapeutic index, not only prolonging survival but also potentiating the efficacy of standard chemotherapy agents. Its selective toxicity sparing normal healthy hematopoietic cells suggests it may offer a safer and more targeted alternative or adjunct to conventional cytotoxic chemotherapy, whose collateral damage remains a critical limitation in the clinical management of infant leukemia.
Perhaps one of the most clinically impactful findings was acetazolamide’s potential to replace or reduce dependence on cytarabine, a cornerstone chemotherapy drug notorious for its severe and often debilitating side effects, including neurotoxicity and myelosuppression. Given that acetazolamide is an orally available drug with a well-characterized safety profile and decades of use in other conditions such as glaucoma and altitude sickness, its repurposing could dramatically shorten the translational timeline to clinical application, expediting access to more tolerable and effective treatments for young patients.
The implications of this study extend beyond simply identifying new drugs; it underscores the transformative potential of integrating molecular biology with pharmacology to uncover hidden vulnerabilities in malignancies previously deemed intractable. By resurrecting normally suppressed microRNAs and targeting their downstream pathways, the research opens new avenues for precision medicine approaches in pediatric oncology, where patient stratification based on genetic abnormalities like KMT2A rearrangement can guide tailored interventions.
Despite these exciting results, the researchers emphasize that this work is at the preclinical stage. Extensive validation through clinical trials is necessary to determine the safety, optimal dosing regimens, and true efficacy of these drugs—particularly acetazolamide—when applied to human infants with KMT2A::AFF1 positive leukemia. Nevertheless, the convergence of discovery science and drug repurposing strategies showcased here exemplifies a pragmatic and resource-efficient paradigm, potentially accelerating the development of urgently needed therapies for a devastating childhood cancer.
Dr. Katrin Ottersbach, Professor of Developmental Hematology at the University of Edinburgh, expressed optimism about the translational trajectory of these findings, remarking on how the study bridges foundational research with real-world clinical potential. Targeting epigenetic dysregulation with repurposed, clinically approved drugs may pave the way toward transforming the treatment landscape, improving survival outcomes, and markedly enhancing the quality of life for affected infants and their families.
This study represents a significant milestone in pediatric leukemia research, receiving funding support from initiatives including Cancer Research UK, the Kay Kendall Leukemia Fund, the Dutch Cancer Society, and the Fight Kids Cancer Funding Programme. Its publication in the peer-reviewed journal HemaSphere offers a detailed account of the experimental methodologies and molecular insights that underpin this promising therapeutic innovation.
As childhood cancers like infant BCP-ALL are relatively rare, collaborative, multinational efforts remain crucial to pool expertise, patient cohorts, and resources necessary for advancing these novel therapeutic approaches into routine clinical use. The repurposing of well-known pharmacological agents provides a beacon of hope for overcoming the current therapeutic impasse, potentially setting new standards for the treatment of genetically defined pediatric malignancies.
Subject of Research: Animals
Article Title: Not provided
News Publication Date: Not provided
Web References: https://onlinelibrary.wiley.com/doi/10.1002/hem3.70353
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Keywords: Pediatric leukemia, KMT2A::AFF1, BCP-ALL, microRNAs, acetazolamide, drug repurposing, preclinical study, infant cancer, targeted therapy, hematology, cancer biology, chemotherapy alternatives
