Unfortunately, the clinical utility of vitamin D in differentiation therapy for leukemia has been hampered by vitamin D-induced hypercalcemia due to the therapeutic levels of vitamin D. In the present work we evaluated if RRD-251 is able to enhance vitamin D3-induced differentiation of leukemic cells, as a proof of principle that intervention in c-Raf- associated pathways using combination therapy can be more effective than D3 alone. Here, RAF1 is linked to leukemia.