(A) In normal lymphopoiesis, DYRK1A targets cyclin D3 for degradation, allowing lymphocytes to become quiescent and differentiate. DRYK1A also phosphorylates FOXO1 for degradation, while the remaining FOXO1 enters the nucleus to sense DNA damage, delay the cell cycle, and repair damage. DYRK1A also phosphorylates STAT3, enabling STAT3 to repress mitochondrial ROS. (B) Trisomy 21 or DYRK1A polyploidy results in overexpression of DYRK1A and increased phosphorylation of DYRK1A and its substrates (cyclin D3, FOXO1, STAT3). In B-ALL, FOXO1 and STAT3 are frequently overexpressed, contributing to even higher levels of phosphorylated FOXO1 and STAT3 when the DYRK1A copy number is increased. The resulting disruptions in cell-cycle progression and decreases in mitochondrial ROS promote leukemogenesis. (C) Inhibition of DYRK1A reduces phosphorylation of DYRK1A and cyclin D3, allowing for cell-cycle progression and chemosensitivity. Inhibition of nuclear FOXO1 also facilitates cell-cycle progression, while blocking repair, thereby fostering chemosensitivity. Blocking STAT3 increases mitochondrial ROS, which could promote B-ALL cell death.