Additional genetic mutations in PML-RARA in patients showing an As₂O₃ refractory/resistant phenotype. (A) Clinical course of patient 1, who showed As₂O₃ resistance in the terminal stage of disease progression. The total clinical duration of the patient was almost 7 years. Detailed information is described in “Methods.” Black and gray arrows indicate the course of chemotherapies with ATRA, As₂O₃, and Am80. The letters A-C enclosed in circles indicate clinically important time points: A indicates diagnosis with APL, B indicates relapse with inadequate response to ATRA, and C indicates confirmation of clinical As₂O₃ resistance. This patient died of disease progression. Leukemia cells from the bone marrow and peripheral blood were obtained at time periods 1-5. Genetic mutations in PML-RARA were confirmed in patients 1 (B) and 6 (C). Missense point mutations in the PML B2 domain and RARA LBD domain were confirmed in the leukemia cells from time point 5. DNA sequences and the genetic code are indicated in capital letters. Bold letters indicate mutations. (D) The zinc finger motif of the PML-B2 domain. Amino acid substitutions in patients 1 and 6 are depicted. The CC motif critical for As₂O₃ binding²⁵  is also indicated. The “C” and “H” in red are the cysteine and histidine, respectively, which are important for zinc finger formation.