Hypermethylation of the Ink4b locus in murine myeloid leukemia and increased susceptibility to leukemia in p15(Ink4b)-deficient mice.
The Ink4b gene (Cdkn2b) encodes p15(Ink4b), a cyclin-dependent kinase inhibitor. It has been implicated in playing a role in the development of acute myeloid leukemia (AML) in man, since it is hypermethylated with high frequency. We provide evidence that the gene is a tumor suppressor for myeloid leukemia in mice. The evidence is twofold: (1) retrovirus-induced myeloid leukemias of the myelomonocytic phenotype were found to have hypermethylation of the 5' CpG island of the Ink4b gene, and this could be correlated with reduced mRNA expression, as demonstrated by TaqMan real-time PCR. p15(Ink4b) mRNA expression in a leukemia cell line, with hypermethylation at the locus, was induced following treatment with 5-aza-2'-deoxycytidine. (2) Targeted deletion of one allele in mice by removal of exon 2 increases their susceptibility to retrovirus-induced myeloid leukemia. Mice deficient in both alleles were not more susceptible to myeloid disease than those deficient in one allele, raising the possibility that there are opposing forces related to the development of myeloid leukemia in Ink4b null mice.
Wolff
Linda
L
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA. lwolff@helix.nih.gov
Garin
Matthew T
MT
Koller
Richard
R
Bies
Juraj
J
Liao
Wei
W
Malumbres
Marcos
M
Tessarollo
Lino
L
Powell
Douglas
D
Perella
Christine
C
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015139:Blotting, Southern; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D005091:Exons; D017353:Gene Deletion; D005838:Genotype; D007438:Introns; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D025521:Tumor Suppressor Proteins
D000964:Antimetabolites, Antineoplastic; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D001374:Azacitidine