After the demonstration that hnRNP K and SET are overexpressed in the APL patients compared with controls, in the present study we knocked down these proteins in both ATRA‐sensitive (NB4) and ATRA‐resistant (NB4‐R2) cell lines by short‐hairpin RNA interference (shRNA) and assessed their involvement in ATRA‐induced cell differentiation, as well as their contributions to the maintenance and survival of leukemic cells. The gene discussed is SET; the disease is acute promyelocytic leukemia.