Mentor Name: Yang Ding

Current targeted strategies for relapsed pediatric B-ALL include targeted agents such as menin inhibitors for KMT2A-rearranged (r) leukemias, but durable responses remain challenging, highlighting the need for rational combination therapies. At the same time, conventional in vitro leukemia cultures do not capture the multicellular interactions, cytokine gradients, and niche cues of the bone marrow microenvironment that can shape therapy responses. The Ding laboratory has established a human induced pluripotent stem cell (iPSC)-derived three-dimensional (3D) human bone marrow organoid (BMO) system to better recapitulate the human hematopoietic niche. The Ding lab also recently described a senescence-associated stem/progenitor-like (SAS) subpopulation regulated by AP-1 transcription factors in KMT2A-r leukemias. We hypothesize that these SAS cells represent a resistant, dormant, plastic subpopulation that may be responsible for leukemia resistance and relapse. Of particular clinical relevance, this SAS gene signature is enriched in higher-risk B-ALL subtypes with high lineage plasticity (with ability to transform from ALL into AML), with highest proportions of SAS cells seen in patients harboring KMT2A rearrangements. In this project, we will investigate whether inhibiting pathways regulated by AP-1 by targeting JNK or AP1 factors using novel inhibitors, can improve therapeutic responses when combined with current targeted approaches such as menin inhibitors in KMT2A-r pediatric B-ALL.