title: Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia.
abstract: Inactivation of p15INK4b, an inhibitor of cyclin-dependent kinases, through DNA methylation is one of the most common epigenetic abnormalities in myeloid leukemia. Although this suggests a key role for this protein in myeloid disease suppression, experimental evidence to support this has not been reported. To address whether this event is critical for premalignant myeloid disorders and leukemia development, mice were generated that have loss of p15Ink4b specifically in myeloid cells. The p15Ink4b(fl/fl)-LysMcre mice develop nonreactive monocytosis in the peripheral blood accompanied by increased numbers of myeloid and monocytic cells in the bone marrow resembling the myeloproliferative form of chronic myelomonocytic leukemia. Spontaneous progression from chronic disease to acute leukemia was not observed. Nevertheless, MOL4070LTR retrovirus integrations provided cooperative genetic mutations resulting in a high frequency of myeloid leukemia in knockout mice. Two common retrovirus insertion sites near c-myb and Sox4 genes were identified, and their transcript up-regulated in leukemia, suggesting a collaborative role of their protein products with p15Ink4b-deficiency in promoting malignant disease. This new animal model demonstrates experimentally that p15Ink4b is a tumor suppressor for myeloid leukemia, and its loss may play an active role in the establishment of preleukemic conditions.
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. biesj@mail.nih.gov
authors.forename: Juraj
authors.initials: J
authors.lastname: Bies
authors.forename: Marek
authors.initials: M
authors.lastname: Sramko
authors.forename: Joanna
authors.initials: J
authors.lastname: Fares
authors.forename: Michael
authors.initials: M
authors.lastname: Rosu-Myles
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Koller
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D016147:Genes, Tumor Suppressor / Q000502:physiology; D020570:Genes, myb / Q000502:physiology; D020022:Genetic Predisposition to Disease; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D055017:Monocyte-Macrophage Precursor Cells / Q000473:pathology / Q000502:physiology; D009000:Monocytes / Q000473:pathology / Q000502:physiology; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology*; D012190:Retroviridae / Q000235:genetics; D055751:SOXC Transcription Factors / Q000235:genetics; D013154:Spleen / Q000473:pathology
chemical_list: C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse
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