Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis

*Department of Pathology,
^§Dana–Farber/Harvard Cancer Center and Department of Laboratory Medicine, Children's Hospital Boston and
^†Joint Program in Transfusion Medicine, Harvard Medical School, Boston, MA 02115; and
^‡Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Rue desProfesseurs Jeener et Brachet 12, 6041 Gosselies, Belgium

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 31, 2008 (received for review January 8, 2008)

Abstract

Inositol trisphosphate 3-kinase B (InsP3KB) belongs to a family of kinases that convert inositol 1,4,5-trisphosphate (Ins(1,4,5)P3 or IP3) to inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4). Previous studies have shown that disruption of InsP3KB leads to impaired T cell and B cell development as well as hyperactivation of neutrophils. Here, we demonstrate that InsP3KB is also a physiological modulator of myelopoiesis. The InsP3KB gene is expressed in all hematopoietic stem/progenitor cell populations. In InsP3KB null mice, the bone marrow granulocyte monocyte progenitor (GMP) population was expanded, and GMP cells proliferated significantly faster. Consequently, neutrophil production in the bone marrow was enhanced, and the peripheral blood neutrophil count was also substantially elevated in these mice. These effects might be due to enhancement of PtdIns(3,4,5)P3/Akt signaling in the InsP3KB null cells. Phosphorylation of cell cycle-inhibitory protein p21^cip1, one of the downstream targets of Akt, was augmented, which can lead to the suppression of the cell cycle-inhibitory effect of p21.

Footnotes

^¶To whom correspondence should be addressed at:
Karp Family Research Building, Room 10214, Boston, MA 02115.
E-mail: hongbo.luo{at}childrens.harvard.edu
Author contributions: Y.J., H.H., and H.R.L. designed research; Y.J., F.L., H.H., and Y.L. performed research; C.E., S.-Y.P., C.G., L.C., L.E.S., and S.S. contributed new reagents/analytic tools; Y.J. and H.R.L. analyzed data; and Y.J. and H.R.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.