Biophysical Regulation of Molecular Pathways in Developmental Hematopoiesis and Cancer

Understanding mechanisms of blood cell regulation in development and cancer is of enormous clinical value.

To study how biophysical cues govern human hematopoiesis, I recently simulated embryonic blood flow in cell culture and identified a role for YAP signaling in hematopoietic stem cell formation in a RUNX1-dependent manner. The transcription factor RUNX1 is required for definitive hematopoiesis, and is frequently mutated in blood diseases.

Inherited RUNX1 mutations cause a platelet disorder with high risk of developing myeloid malignancies.

Despite its known role as a key player in leukemic transformation, the effect of RUNX1 mutations, as well as strategies to block disease progression and restore functional hematopoiesis, remain unknown.Induced pluripotent stem cells (iPSCs) will be used to model normal and leukemic hematopoiesis, allowing us to map multi-omics networks to specific stages of differentiation and disease progression.

Specifically, we will define temporal regulation of YAP-RUNX1 in normal hematopoiesis.

Furher, we aim to develop unique patient-derived iPSC lines harboring germline RUNX1 mutations, in order to study molecular pathogenesis of leukemia.

By manipulating distinct stem cell populations and signaling pathways in our system, we will identify predictors of prognosis and targets for drug development.

We hope that our research will lead to new, more efficient therapies for patients with RUNX1 mutations and hematological malignancies as a whole.