Exploiting novel therapeutic vulnerabilities in infant acute lymphoblastic leukemia (ALL)

• Applicant: Dr. Katharina Daugs
• Subject Area: Pediatric and Adolescent Medicine ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564694041

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood, with cure rates now exceeding 90%. However, certain high-risk subtypes, such as KMT2A-rearranged (KMT2A-r) ALL, formerly known as Mixed Lineage Leukemia (MLL), are associated with significantly worse prognoses. KMT2A, located on chromosome 11q23, undergoes rearrangement through a single translocation event with over 100 partner genes. This KMT2A-r subtype occurs in 80% of infants with B-cell precursor (BCP)-ALL and is characterized by a high propensity for involvement of the central nervous system (CNS), poor treatment response, and aggressive relapse risk, ultimately leading to a 5-year event-free survival (EFS) rate of 49.4% (Interfant-06 study). Although the addition of Blinatumomab (a bispecific T-cell engager) has shown a promising improvement in 2-year EFS in recent studies, its limited CNS penetration poses ongoing challenges in treating KMT2A-r infant ALL. These findings underscore the urgent need to better understand the underlying pathomechanisms and develop innovative therapeutic approaches. Dysregulated expression of fetal genes such as LIN28B, HOXB4, and IGF2BP1 appears critical for KMT2A-mediated leukemogenesis. Furthermore, Polo-like kinase 1 (PLK1), a serine-threonine kinase involved in mitotic cell cycle regulation, has been identified as essential for the survival of KMT2A-r leukemic cells and is remarkably overexpressed in the bone marrow of ALL patients. Building on this, we identified PLK1-inhibitors (PLK1-i) such as Volasertib and BI2536 as highly effective against high-risk leukemias in an ex vivo high-throughput drug screening (HTDS). Prior research further indicates that PLK1-i, when combined with chemotherapeutic agents, induce synergistic apoptotic effects in leukemia cells and may prevent the emergence of resistant clones that compromise the efficacy of monotherapies. Moreover, combining PLK1-i with histone- deacetylase inhibitors (HDAC-i) has shown potential, as HDAC-i target specific epigenetic vulnerabilities in KMT2A-r leukemias. Both PLK1-i and HDAC-i have demonstrated the ability to cross the blood-brain barrier, which could significantly impact the future treatment of KMT2A-r infant ALL in combination with Blinatumomab, particularly in cases with CNS involvement. This study aims to (1) evaluate the efficacy of PLK1-i in a unique CRISPR-Cas-generated KMT2A-AFF1 BCP-ALL model, recently established in the laboratory of Prof. A. Roy, University of Oxford, UK., (2) conduct high-throughput drug screenings to identify potential combination partners (e.g., HDAC-i), and (3) investigate the mechanisms of action of the most promising compounds. Ultimately, the goal is to evaluate novel therapeutic approaches for KMT2A-r infant ALL with CNS involvement, aiming to sustainably improve outcomes for this high-risk group.

• DFG Programme: WBP Fellowship
• International Connection: United Kingdom
• Host: Professorin Dr. Anindita Roy