Cobalt chloride and low oxygen tension trigger differentiation of acute myeloid leukemic cells: possible mediation of hypoxia-inducible factor-1alpha.

Cellular and systemic O(2) concentrations are tightly regulated to maintain delicate oxygen homeostasis. Although the roles of hypoxia in solid tumors have been widely studied, few studies were reported regarding the possible effects of hypoxia on leukemic cells. Here, we showed for the first time that low concentrations of cobalt chloride (CoCl(2)), a hypoxia-mimicking agent, and 2-3% O(2) triggered differentiation of various subtypes of human acute myeloid leukemic (AML) cell lines, including NB4, U937 and Kasumi-1 cells, respectively, from M3, M5 and M2b-type AML, but CoCl(2) did not modulate AML subtype-specific fusion proteins promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) and AML1-ETO. Treatment with CoCl(2) also induced primary leukemic cells from some AML patients to undergo differentiation. Similar to what occurs in solid tumor cells, CoCl(2)-mimicked hypoxia also increased the level of hypoxia-inducible factor (HIF)-1alpha protein and its DNA-binding activity in leukemic cells. The CoCl(2) induction of HIF-1alpha protein and its DNA-binding activity were inhibited by 3-morpholinosydnonimine, which also blocked CoCl(2)-induced cell differentiation in leukemic cells. These results provide an insight into a possible link of hypoxia or HIF-1alpha and leukemic cell differentiation, and are possibly of significance to explore clinical potentials of hypoxia or hypoxia-mimicking agents and novel target-based drugs for differentiation therapy of leukemia.