MUTATIONS IN THE P53 AND RAS FAMILY GENES ARE ASSOCIATED WITH TUMOR PROGRESSION OF BCR ABL NEGATIVE CHRONIC MYELOPROLIFERATIVE DISORDERS

We have investigated the involvement of the p53 tumor suppressor gene and RAS family proto-oncogenes. in BCR/ABL-negative chronic myeloproli ferative disorders (CMPD), including nine cases of myelosclerosis with myeloid metaplasis, four polycythemia vera, 10 essential thrombocythe mia, one juvenile chronic myeloid leukemia, and eight BCR/ABL-negative chronic myeloid leukemia. Twenty-five samples were studied in the chr onic phase, while seven samples were analyzed in the acute accelerated or blastic phase. The presence of mutations in p53 exons 5-9, as well as in N-, K-, H-Ras exons 1 and 2 (containing codons 12,13, and 61) w as tested by the polymerase chain reaction (PCR) single strand conform ation polymorphism technique and by PCR direct sequencing. In addition , restriction analysis was performed to screen for gross rearrangement s within the p53 locus. Alterations of the p53 tumor suppressor gene a nd Ras family proto-oncogenes were detected in 2/7 and 3/7 cases of ac ute phase BCR/ABL-negative CMPD, respectively, while consistently nega tive in all the chronic phase samples analyzed. These results suggest that p53 inactivation and/or Ras activation might play a role in acute transformation of BCR/ABL-negative CMPD.