JmjC‐domain containing histone demethylase 1B‐mediated p15 Ink4b 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)...

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Veröffentlicht in:Molecular carcinogenesis 2013-01, Vol.52 (1), p.57-69
Hauptverfasser: Nakamura, Satoki, Tan, Lin, Nagata, Yasuyuki, Takemura, Tomonari, Asahina, Aya, Yokota, Daisuke, Yagyu, Tomohiro, Shibata, Kiyoshi, Fujisawa, Shinya, Ohnishi, Kazunori
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Sprache:eng
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Zusammenfassung: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 ALDH hi (high aldehyde dehydrogenase activity)/CD34 + cells, the levels of JHDM1B mRNA were significantly higher than in normal ALDH hi /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 p15 Ink4b 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 ALDH hi /CD34 + cells, JHDM1B gene expression was 1.57‐ to 1.87‐fold higher in AML‐derived ALDH hi /CD34 + cells. Moreover, the JHDM1B protein was more strongly expressed in AML‐derived ALDH hi /CD34 + cells from compared to normal ALDH hi /CD34 + cells. In addition, depletion of JHDM1B reduced colony formation of AML‐derived ALDH hi /CD34 + cells due to induction of p15 Ink4b expression through direct binding to p15 Ink4b promoter and loss of demethylation of H3K36me2. In summary, we found that JHDM1B mRNA is predominantly expressed in AML‐derived ALDH hi /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. © 2011 Wiley Periodicals, Inc.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.20878