Primary sorafenib-resistant AML samples were dependent on NHE1 for survival. (A) Six out of 7 sorafenib-resistant AML samples exhibited higher pHi compared with their sorafenib-naïve counterparts. (B) HMA had minimal suppressive effects on normal hematopoietic cells but significantly suppressed sorafenib-resistant myeloblasts and to a lesser extent sorafenib-naïve AML cells. (C) HMA treatment had no effect on the engrafting potential of HSCs from umbilical CB. (D) HMA treatment at the same dose in (i) MOLM-13 and (ii) MV4-11 nearly abolished leukemia engraftment in NOD/SCID mice. (E) Both HMA and sorafenib reduced leukemia engraftment by MOLM-13 (blue column), and their combination completely abolished the engraftment. For M13-RE (red column), sorafenib treatment had no effect on human engraftment. HMA reduced leukemia engraftment and when combined with sorafenib completely abolished leukemia engraftment. (F) HMA significantly reduced human engraftment from (i) sorafenib-naïve and (ii) sorafenib-resistant primary FLT3-ITD+ AML compared with the vehicle control.
