Fig. 6: Kinase-dependent activation of NHE1 in AML and overcoming aberrant pHi by therapeutic means.

In kinase-activated AML, NHE1 was phosphorylated and activated by kinase cascade and pHi became alkaline. The latter enhanced leukemia growth and reduced the intracellular distribution of therapeutic agents such as kinase inhibitors and chemotherapy. NHE1 could be inhibited by amiloride or kinase inhibitors that inhibited its upstream activators. These treatments reduced pHi and hence reversed the pathogenetic processes of leukemia and increased intracellular distribution of therapeutic agents.