P53, p15(INK4B), p16(INK4A) and p57(KIP2) mutations during the progressionof chronic myeloid leukemia

The occurrence of acute transformation during the treatment of chronic myel oid leukemia (CML) is still a poorly understood mechanism. In this disease p53, p16(INK4A), p15(INK4B), p57(KIP2) mutations and p15(INK4B)/p16(INK4A), homo/hemizygous deletions were analyzed in the initial diagnosis phase and during the treatment phase of twelve CML cases, in order to establish whet her there was a consistent molecular genetic alteration in its progression. During the treatment period, four of twelve cases had blastic crisis. All the mutations observed in p53, p16(INK4A) and p15(INK4B) cumulated in three out of four CML cases who had blastic crises. In one case, p53 codon 282 m utation (CGG-->TGG; arg-->trp) were observed in initial diagnosis. Seven mo nths later, G-->C transition in the 3' side of p15 cDNA (778. nucleotide) w as observed in the accelerated phase with the same p53 codon 282 mutation. Thirteen months later, this patient died as a result of blastic crisis. The patient in blastic crises in the initial diagnosis phase had a mis-sense p oint mutation in p16 codon 69 (ACT --> AGT; thr --> ser) and a polymorphism in codon 68 (GCC --> GCG). Six months later, this patient also died. In on e case, p53 codon 237 mutation (ATG --> ATA; met --> ile) were observed in the initial diagnosis phase. Then months later, the patient died as a resul t of blastic crises. No p15(INK4B)/p16(INK4A) homo/hemizygous deletion and p57KIP2 gene mutation which was described in the same pathway were observed in CML progression. These results indicate that p15(INK4B) and p16(INK4A) gene alterations may have an affect on the progression of CML-like p53 muta tion. A correlation was found with the progression of CML and p53, p16(INK4 B) and p16(INK4A) somatic mutations. Finding p15(INK4B) and p16(INK4A) gene alteration as well as p53 mutations may be a prognostic marker in patients with CML.