DYRK1A is a novel target in B-cell leukemia

Aim 1: Determine the requirements for DYRK1A in human DS and non-DS B-ALL. We will use both genetic and pharmacologic approaches to determine the requirement for DYRK1A in malignant B-cells. Our goal is to generate pre-clinical data to support further development of DYRK1A inhibitors as a new therapy. Aim 2: Identify the mechanisms by which DYRK1A inhibition causes growth inhibition of ALL cells. We will first study the manner in which the inhibitors impede the growth of ALL cells and assess whether reduced phosphorylation of caspase 9, a known substrate of DYRK1A, contributes to increased cell death of the leukemia cells. Second, we will use an unbiased approach to identify novel substrates of DYRK1A in ALL cells. Our long-term goal is to test DYRK1A kinase inhibitors in pre-B ALL in a Phase I study.