Loss of the tumor suppressor p15Ink4b enhances myeloid progenitor formation from common myeloid progenitors.
OBJECTIVE
The tumor suppressor p15Ink4b (Ink4b) is a cell-cycle inhibitor that is inactivated in a high percentage of acute myeloid leukemia and myeloid dysplasia syndrome cases. Despite this, the role of Ink4b in hematopoiesis remains unclear. Here we examined the role of Ink4b in blood cell formation using Ink4b-deficient (Ink4b(-/-)) mice.


METHODS
We compared the bone marrow (BM) of Ink4b(-/-) and wild-type mice using flow cytometric, colony-forming unit and competitive repopulating assays (CRA). The proliferation, differentiation, self-renewal, and apoptosis of progenitor cells were further compared by in vitro and in vivo methods.


RESULTS
BM from Ink4b(-/-) mice contained increased numbers of granulocyte-monocyte progenitors and Gr-1(+) cells and showed a competitive advantage over wild-type cells in myeloid cell formation by CRA. Ink4b(-/-) progenitors did not demonstrate increased proliferation, self-renewing potential, or reduced apoptosis. Instead, Ink4b(-/-) common myeloid progenitors (CMPs) showed increased myeloid progenitor formation concomitant with reduced erythroid potential.


CONCLUSIONS
This work establishes a role for Ink4b in regulating the differentiation of CMPs and indicates that loss of Ink4b enhances the formation of myeloid progenitors.
Rosu-Myles
Michael
M
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4263, USA.
Taylor
Barbara J
BJ
Wolff
Linda
L
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay / Q000379:methods; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000172:deficiency* / Q000502:physiology*; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000166:cytology* / Q000502:physiology
C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15