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p16ink4a gene and hematological malignancies
B Quesnel1, C Preudhomme, P Fenaux
1Service des maladies du sang CHU Lille, France.
Abstract:
Progression of eukaryotic cells through major cell cycle transitions is mediated by sequential assembly and activation of regulators, the cyclin-dependent CDKkinases (CDKs). Recent studies have identified different CDK inhibitory genes (CDKis), and two of them, p16ink4a/MTS1/CDKN2 and p15ink4b/MTS2 are both mapped to chromosome 9p21 and inhibit cyclin D-CDK4 and -CDK6 complexes. A feedback regulatory loop involving pRb, p16ink4a, and CDKs seems to regulate G1/S phases transition. p16ink4a and p15ink4b are deleted in high frequency in human cell lines and in some fresh solid tumors. Point mutations of p16ink4a have also been sequenced, especially in familial melanomas and digestive cancers but preferential mechanism of p16ink4a/p15ink4b inactivation seems to be biallelic deletion. In hematological malignancies, homozygous deletions of p16ink4a and p15ink4b occur frequently in acute lymphoblastic leukemia (ALL) (14-40%), lymphoid type blast crisis of chronic myeloid leukemia (CML), and adult T cell leukemia (ATL), but p16ink4a deletions are more frequent than p15ink4b deletions, and hemizygous deletions of either p16ink4a and p15ink4b are rare. In ALL an association of homozygous deletions of p16ink4a and p15ink4b, and T-lineage, 9p abnormalities, and prognostic factors was found in some but not all reports. This review presents recent data on p16ink4a and p15ink4b functions and analyses their implications in hematological malignancies.
Insights
The p16ink4a and p15ink4b genes, critical for cell cycle regulation, are frequently deleted in hematological malignancies like acute lymphoblastic leukemia. Their inactivation, primarily through deletion, impacts cancer progression and offers therapeutic targets.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Cell cycle progression relies on cyclin-dependent kinases (CDKs) and their regulators.
- CDK inhibitors (CDKis), including p16ink4a and p15ink4b, are crucial for controlling cell division.
- These genes are located on chromosome 9p21 and are frequently altered in various cancers.
Purpose of the Study:
- To review the functions of p16ink4a and p15ink4b.
- To analyze the implications of p16ink4a and p15ink4b alterations in hematological malignancies.
- To highlight the role of these genes in cell cycle regulation and cancer development.
Main Methods:
- Literature review of recent studies on p16ink4a and p15ink4b.
- Analysis of genetic alterations (deletions, mutations) in cancer cell lines and tumors.
- Examination of functional data regarding CDK inhibition and cell cycle control.
Main Results:
- p16ink4a and p15ink4b inhibit cyclin D-CDK4/6 complexes, regulating the G1/S phase transition.
- Biallelic deletion is the predominant mechanism for p16ink4a/p15ink4b inactivation in cancers.
- Homozygous deletions are frequent in acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) blast crisis, and adult T-cell leukemia (ATL), with p16ink4a deletions being more common.
Conclusions:
- p16ink4a and p15ink4b play a significant role in cell cycle control and are frequently inactivated in hematological malignancies.
- The high frequency of deletions in ALL suggests their importance in leukemogenesis.
- Understanding these genetic alterations is vital for comprehending cancer progression and developing targeted therapies.