Myeloid-specific inactivation of p15Ink4b results in monocytosis and predisposition to myeloid leukemia.
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.
Bies
Juraj
J
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. biesj@mail.nih.gov
Sramko
Marek
M
Fares
Joanna
J
Rosu-Myles
Michael
M
Zhang
Steven
S
Koller
Richard
R
Wolff
Linda
L
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
C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse
Blood. 2007 Aug 15;110(4):1251-61
17452517
Exp Hematol. 2007 Mar;35(3):394-406
17309820
Nat Rev Cancer. 2003 Feb;3(2):89-101
12563308
Blood. 1999 Oct 1;94(7):2445-51
10498617
Br J Cancer. 2009 Feb 10;100(3):511-23
19156145
Am J Clin Pathol. 2005 Nov;124(5):799-806
16203279
Blood. 1997 Aug 15;90(4):1403-9
9269757
Cancer Res. 1996 Feb 15;56(4):722-7
8631003
Eur J Haematol. 2006 Jan;76(1):23-32
16343268
Transgenic Res. 1999 Aug;8(4):265-77
10621974
J Neurooncol. 2002 May;57(3):201-14
12125983
Leukemia. 2003 May;17(5):910-8
12750705
Nat Genet. 2007 May;39(5):593-5
17435759
Biochim Biophys Acta. 2002 Mar 14;1602(1):73-87
11960696
Nature. 2007 Aug 23;448(7156):943-6
17713536
Virology. 1996 Oct 1;224(1):224-34
8862417
Hum Mol Genet. 2009 Apr 1;18(7):1343-52
19153074
Oncogene. 2003 Dec 18;22(58):9265-74
14681685
Oncogene. 1999 May 13;18(19):3017-33
10378697
Blood. 2002 Jul 1;100(1):246-58
12070034
Virology. 1994 Dec;205(2):479-85
7975249
Leukemia. 1998 Jun;12(6):845-59
9639410
Leukemia. 2009 Jan;23(1):85-94
18818702
J Natl Cancer Inst. 1999 Jan 6;91(1):73-9
9890173
J Virol. 1999 Mar;73(3):2038-44
9971784
Oncogene. 1989 May;4(5):583-92
2471131
Cancer Res. 2007 Jun 1;67(11):5148-55
17545593
Leuk Res. 2005 Jun;29(6):653-9
15863205
Cell Stem Cell. 2009 Feb 6;4(2):129-40
19200802
Nature. 1996 Apr 25;380(6576):711-4
8614465
Blood. 2006 Jan 15;107(2):733-41
16204320
Mol Cell Biol. 1992 Jun;12(6):2493-500
1588953
EMBO J. 2000 Jul 3;19(13):3496-506
10880462
J Virol. 2003 Apr;77(8):4965-71
12663802
Best Pract Res Clin Haematol. 2001 Mar;14(1):49-64
11355923
Br J Haematol. 2001 Jan;112(1):148-54
11167795
Blood. 2002 Jul 1;100(1):238-45
12070033
Br J Dermatol. 2006 Nov;155(5):999-1005
17034532
Methods Mol Biol. 2001;158:47-63
11236671
Cell Growth Differ. 1995 Jan;6(1):59-68
7536440