Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features

Abstract

p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 × 10 9 /l vs 271 × 10 9 /l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.

CDKN2 Gene Deletion as Poor Prognosis Predictor Involved in the Progression of Adult B-Lineage Acute Lymphoblastic Leukemia Patients

“…MLL rearrangement is another adverse factor resulting in poor prognosis, the frequency of CDKN2 deletion in MLL rearranged patients was 15.4% in our study, the incidence rate was lower than Ohnishi, H's report 26 . In our research, patients with MLL rearrangement and CDKN2 deletion had a short survival time, especially one patient with both gene alterations died in the early period of induction chemotherapy, and another patient died within 4 months.…”

Inhibition of histone methyltransferase EZH2 depletes leukemia stem cell of mixed lineage leukemia fusion leukemia through upregulation of p16

“…These data support the idea that suppression of p16 is one of the important processes to maintain MLL fusion leukemia, and it is more sensitive to restoration of p16 expression compared with other leukemias. Clinically, chromosomal deletion around p16 is associated with lower survival in MLL rearranged leukemia . The upregulation of p16, which is negatively controlled by EZH2 and Bmi1, is known to be the initial event after transduction of oncogene .…”

“…Clinically, chromosomal deletion around p16 is associated with lower survival in MLL rearranged leukemia. (44) The upregulation of p16, which is negatively controlled by EZH2 and Bmi1, is known to be the initial event after transduction of oncogene. (35,36,45) We suppose that removal of EZH2 at the p16 promoter restores its expression and induces OIS.…”

Pattern ofFHIT gene expression in normal and leukaemic cells

“…Although the mutation of p53 was infrequent in fresh ALL cases, the alteration has been associated with relapse phase or progression of ALL in our previous study (Kawamura et al, 1995). As for the p16 gene, frequent homozygous deletion was found in various types of leukaemia cell lines (Ogawa et al, 1994), and in primary T-ALL and B precursor ALL, but not in acute leukaemia with MLL gene rearrangements (Ohnishi et al, 1997). Deletions at chromosome 3p are common in many human cancers, and at least 4 distinct 3p regions, including 3p12, 3p14, 3p21 and 3p24-25, are believed to harbor tumour suppressor genes Sozzi et al, 1996b).…”