Thrombomodulin-induced differentiation of acute myelomonocytic leukemia cells via JNK signaling

We found recombinant human soluble thrombomodulin (rTM) induced growth arrest and differentiation of THP-1 cells by activating JNK/c-Jun signaling. Further activation of JNK by 1,25-(OH)2D3 significantly enhanced rTM-mediated growth arrest and differentiation of THP-1 cells. Importantly, forced expression of domains 1, 2 and 3 of TM (TMD123) induced growth arrest and differentiation of leukemia cells freshly isolated from individuals with AMLs of M4/M5-French-American-British classification subtypes, but not those with less advanced AML. Further studies indicated that the epidermal growth factor-like domain of TM was critical for the anti-leukemia effects of TM and these effects were independent of protein C activation.