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Molecular analysis of cyclin-dependent kinase inhibitors in human leukemias
S Hayette1, X Thomas, Y Bertrand
1Laboratoire d'Hématologie et de Cytogénétique, Hôpital Edouard Herriot, Lyon, France.
Abstract:
Recurrent anomalies of the short arm of chromosome 9, including interstitial deletions and translocations, have often been described. Recently two cyclin-dependent kinase inhibitors, known as P16 (INK4A/MTS1) and P15 (INK4B/MTS2), which map to 9p21, have been found deleted in a wide range of tumors and particularly in leukemic cells. We report here Southern blot analyses of cyclin-dependent kinase inhibitors (P16, P15, P21, and P27) status in primary tumoral cells of 121 patients with acute lymphoblastic leukemias, 85 patients with acute myeloid leukemias and 42 patients with B-chronic lymphocytic leukemias. P16 inactivation was found in 25 of 38 T-ALLs and in 28 of 83 B-lineage ALLs. In eight cases (three T-ALLs and five B-lineage ALLs), one or both alleles of P16 locus were rearranged. In these cases, breakpoints occurred within the two major breakpoints cluster regions previously described in T-ALLs. Homozygous P16 deletions were observed in two of 85 AMLs but in none of the 42 B-CLL cases tested. Our results suggest that P16 inactivation are the most frequent event observed in ALL (44%), are quite rare in AML (<2%) and seem to be absent in CLL. Search for P27 and P21 deletion was negative in B/T-lineage ALLs and monoallelic deletions of P27 were found in four AML cases (5%).
Insights
P16 gene inactivation is a frequent event in acute lymphoblastic leukemias (ALL), occurring in 44% of cases. This genetic alteration is rare in acute myeloid leukemia (AML) and absent in chronic lymphocytic leukemia (CLL).
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Recurrent chromosomal anomalies in 9p are common in various cancers.
- Cyclin-dependent kinase inhibitors P16 (INK4A/MTS1) and P15 (INK4B/MTS2) located at 9p21 are frequently deleted in tumors, especially leukemic cells.
Purpose of the Study:
- To investigate the status of cyclin-dependent kinase inhibitors (P16, P15, P21, and P27) in primary tumor cells from patients with acute lymphoblastic leukemias (ALL), acute myeloid leukemias (AML), and B-chronic lymphocytic leukemias (B-CLL).
Main Methods:
- Southern blot analysis was employed to assess the status of P16, P15, P21, and P27 genes.
- The study analyzed primary tumor cells from 121 ALL, 85 AML, and 42 B-CLL patients.
Main Results:
- P16 inactivation was observed in 44% of ALL cases (25/38 T-ALLs, 28/83 B-lineage ALLs).
- Eight ALL cases showed P16 locus rearrangements within known breakpoint cluster regions.
- Homozygous P16 deletions were found in 2/85 AML cases, but not in B-CLL.
- P27 deletions were found in 5% of AML cases; P21 and P27 deletions were negative in ALL.
Conclusions:
- P16 inactivation is the most frequent genetic event in ALL, rare in AML, and absent in CLL.
- The findings highlight the significant role of P16 alterations in the pathogenesis of ALL.