Proposed role of TESC/NHE1/pH axis in sorafenib-resistant AML. (A) In sorafenib-resistant AML, TESC was significantly upregulated, leading to increased activity of NHE1, more efflux of H⁺, and hence higher pH_i, increased cellular proliferation and antiapoptosis, reduced intracellular sorafenib level, and unopposed FLT3 activity. The question mark represents a yet to be identified mechanism of NHE1 activity in addition to TESC. (B) With HMA, NHE1 activity was reduced, resulting in lower pH_i, inhibition of proliferation and apoptosis induction, increased intracellular sorafenib level, and more FLT3 inhibition. Lower pH_i also reduced FLT3 signaling directly.