Sahoo Lab

Somatic mutations accumulate with age across all tissues, but the accessibility of blood has made it a powerful window into their dynamics and consequences. While most mutations in hematopoiesis are neutral, some confer a fitness advantage, particularly under selective pressures such as inflammation, immune activation, or genotoxic therapy. The resulting expansion of these “fittest” clones leads to clonal hematopoiesis (CH), a state well recognized in adults as a precursor to hematologic malignancy and early mortality. Research by Dr. Sahoo and others has shown that CH is not confined to old age and can also occur in children, particularly in the context of bone marrow failure (BMF) and leukemia predisposition syndromes. In settings where germline mutations impair hematopoietic stem and progenitor cell (HSPC) fitness and lead to BMF, clonal outgrowth may emerge as a compensatory mechanism to offset the pathogenic effects of the mutant allele. However, certain somatic clones can paradoxically acquire high-risk secondary lesions that drive malignant transformation or therapy resistance, culminating in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or disease relapse.

Despite these profound clinical impacts, the determinants governing clonal origin, fitness, leukemic evolution, and treatment failure in pediatric blood cancers remain poorly defined.

To address these gaps, Dr. Sahoo's research program focuses on three interrelated questions:

1. How do germline mutations impair HSPC function and promote clonal selection?
2. How do certain somatic clones acquire leukemic potential and transform?
3. Can we identify when high-risk molecular signatures emerge during clonal evolution to predict leukemic transformation and therapeutic resistance?

Guided by patient-derived genomic and clinical data, we integrate bulk and single-cell genomic analyses with functional studies in human iPSC and mouse experimental models to address these questions. The lab's long-term goal is to uncover the drivers of leukemic progression and to identify actionable targets for early intervention.