P16(INK4A) AND P15(INK4B) GENE DELETIONS IN PRIMARY LEUKEMIAS

The 9p21 locus has been deleted at a high frequency in a wide variety of tumors. Recently, two genes, p16(INK4A) and p15(INK4B) (also called MTS1 and MTS2), have been localized in close proximity at the 9p21 locus, encoding cyclin-dependent kinases 4/6 inhibitors of relative molecular mass 16 kD and 15 kD, respectively and also found to be deleted at a high frequency in tumor cell lines. We analyzed p16(INK4A) and p15(INK4B) genes in 178 cases of primary leukemias including 81 cases of chronic lymphocytic leukemia (CLL), seven of hairy cell leukemia (HCL), seven of chronic myelogenous leukemia (CML), 43 of acute myelogenous leukemia (AML), 27 of acute lymphoblastic leukemia (ALL), and 13 of myelodysplastic syndrome (MDS) by Southern blot analyses. The ALL cases showed a relatively high frequency of homozygous deletions (22%, 6 of 27) at the p16(INK4A) gene locus. Interestingly, of the six cases with p16(INK4A) homozygous deletions, only three showed homozygous deletions at the p15(INK4B) gene. In 81 CLL patients, we detected one homozygous and five heterozygous deletions at both the p16(INK4A) and p15(INK4B) genes and two heterozygous deletions at the p16(INK4A) gene alone. Deletion of these two genes in AML cases is relatively low (9%). We did not detect deletions in any of the MDS, HCL, and CML cases examined. Sequence analyses of p16(INK4A) gene of six CLL cases with heterozygous deletion at this locus showed a 27-bp deletion at the splice acceptor site of intron 1 in one case and changes in the coding sequence in three other cases. The data presented in this report showed that (1) p16(INK4A) and p15(INK4B) genes are preferentially deleted homozygously in ALL and heterozygously in CLL cases with frequent mutation in the second allele, and (2) p16(INK4A) gene appears to be more frequently deleted than p15(INK4B) gene. (C) 1995 by The American Society of Hematology.