JmjC-domain containing histone demethylase 1B-mediated p15Ink4b suppression promotes the proliferation of leukemic progenitor cells through modulation of cell cycle progression in acute myeloid leukemia

The histone demethylase JHDM1B has been implicated in cell cycle regulation and tumorigenesis. In addition, it has been reported that JHDM1B is highly expressed in various human tumors, including leukemias. However, it is not clearly understood how JHDM1B contributes to acute myeloid leukemia (AML) cell proliferation. In this study, we investigated the cellular and molecular function of JHDM1B in AML cells. In AML cell lines and AML-derived ALDHhi (high aldehyde dehydrogenase activity)/CD34+ cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDHhi/CD34+ cells. Reduction of JHDM1B expression in AML cells inhibited cell proliferation compared to control cells, through induction of G1 cell cycle arrest, an increase in the p15Ink4b mRNA and protein expression. JHDM1B mRNA was overexpressed in all 133 AML clinical specimens tested (n?=?22, 57, 34, and 20 for M1, 2, 4, and 5 subtypes respectively). Compared to normal ALDHhi/CD34+ cells, JHDM1B gene expression was 1.57- to 1.87-fold higher in AML-derived ALDHhi/CD34+cells. Moreover, the JHDM1B protein was more strongly expressed in AML-derived ALDHhi/CD34+ cells from compared to normal ALDHhi/CD34+ cells. In addition, depletion of JHDM1B reduced colony formation of AML-derived ALDHhi/CD34+ cells due to induction of p15Ink4b expression through direct binding to p15Ink4b promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML-derived ALDHhi/CD34+ cells, and that aberrant expression of JHDM1B induces AML cell proliferation through modulation of cell cycle progression. Thus, inhibition of JHDM1B expression represents an attractive target for AML therapy. (c) 2011 Wiley Periodicals, Inc.