Project Details

Defining the Clinical Spectrum and Mechanism of TUBB-Mediated Pediatric Bone Marrow Failure

Nicholas Lee, MD

Summary

BACKGROUND: Pediatric bone marrow failure (BMF) is a life-threatening condition that presents with cytopenias due to immune-mediated destruction of hematopoietic stem/progenitor cells (HSPC) or inherited HSPC dysfunction. Correct diagnosis of inherited BMF is essential because it informs family counseling, hematopoietic cell transplantation (HCT) donor selection, and HCT appropriateness. GAP: The genetic spectrum, clinical phenotype (including treatment-response), and mechanism of tubulin variants in pediatric BMF are unknown. HYPOTHESIS: Children with aplastic anemia or thrombocytopenia may harbor a causal tubulin variant. Tubulin variants will produce microtubule-dependent HSPC and megakaryocyte dysfunction. METHODS: We will use our existing BMF biorepository to perform whole genome sequencing. Based on any variants identified, we will model those variants to quantify HSPC fitness (CD34+ selected colony forming unit assays), characterize MPL surface expression (flow cytometry), and establish an induced pluripotent stem cell model. RESULTS: Pending. IMPACT: By defining the genetic spectrum, clinical phenotype, and mechanism of tubulin variants in pediatric BMF, this work will directly improve outcomes in children by preventing inappropriate related-donor transplantation, enabling earlier genetic diagnosis, and guiding pediatric-specific management strategies for bone marrow failure. Website Link: https://www.linkedin.com/in/nicholascjlee