TAcute myeloid leukemia (AML) treatment remains highly variable, with survival improvement lagging in adolescent and young adult (AYA) patients compared to children and older adults. Among these, both germline and somatic RUNX1 mutations are independently associated with poor outcomes. RUNX1-mutated familial platelet disorder (FPD), nearly 40-50% of patients aged 11–40 progress to leukemia. Children with FPD experience lifelong bleeding and immune disorders, impacting their daily lives. Recent estimates suggest that ~18,000 individuals may have RUNX1-FPD, yet no interventions exist to prevent leukemic transformation.
Our research indicates that many inflammatory cytokines are high in FPD. We prioritized clinically targetable inflammatory pathway TNF-a, which regulates mTOR and JAK1/2 signaling. Our efforts led to the first clinical trial for mTOR inhibitor sirolimus in FPD to improve blood cell functions. Our preliminary data suggest that TNF-a inhibition may reduce preleukemic cell growth and improve differentiation of blood cells in RUNX1-FPD. Here, we will conduct preclinical testing of TNFa inhibitors using murine models and young patient samples in cell culture and in vivo models. We will evaluate the effect of TNF-a inhibition on stem cells and immune cell functions. TNF-a inhibitors such as etanercept and adalimumab are already FDA-approved for autoimmune diseases and have favorable safety profiles, enabling rapid clinical repurposing.
Overall, we will test the hypothesis that targeting TNF-mediated inflammatory pathways can delay leukemia progression and improve immune function in young patients. Our overarching objectives will be to 1) identify the impact of TNF-a inhibitors on stem cell functions, leukemia progression, and immune dysregulation in FPD, defining prognostic and therapeutic markers. 2) Validate findings in primary samples. 3) Lay the groundwork for early intervention in FPD to expedite translation to clinical trials by repurposing FDA-approved drugs for TNF-a inhibition. Our study will be critical for designing Phase I clinical trials for RUNX1-FPD patients and may be applicable for pediatric patients with somatic RUNX1 mutations. To achieve our goals, we assembled a multi-disciplinary team of investigators and collaborators, including biologists, clinicians, and bioinformaticians. Additionally, we have unique access to these rare samples and are supported by the robust environment and resources at Knight Cancer Center.
