Limits...
Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

Zhou M, Zeng J, Wang X, Wang X, Huang T, Fu Y, Sun T, Jia J, Chen C - Oncotarget (2015)

Bottom Line: In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP.This in turn activated PDCD4.In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China.

ABSTRACT
Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

Show MeSH

Related in: MedlinePlus

RBP2 induces cell differentiation(A) The mRNA expression of RBP2 in differentiated K562 and HL60 leukemia cells induced by DMSO. Quantitative RT-PCR (qRT-PCR) analysis of the mRNA levels of RBP2, c-myc, and PU.1 and loading control β-actin. Data are mean ± SEM of 3 independent experiments. (B) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with DMSO. β-actin was a loading control. (C) qRT-PCR analysis of RBP2, c-myc, and PU.1 mRNA expression and the loading control β-actin in differentiated cells induced by ATRA. Data are mean ± SEM of 3 independent experiments. (D) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with ATRA. β-actin was a loading control. (E) The mRNA expression of RBP2, c-myc, and PU.1 in differentiated primary cells induced by DMSO. The results are from 3 independent experiments. *P< 0.05, **P< 0.01, ***P< 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4359230&req=5

Figure 1: RBP2 induces cell differentiation(A) The mRNA expression of RBP2 in differentiated K562 and HL60 leukemia cells induced by DMSO. Quantitative RT-PCR (qRT-PCR) analysis of the mRNA levels of RBP2, c-myc, and PU.1 and loading control β-actin. Data are mean ± SEM of 3 independent experiments. (B) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with DMSO. β-actin was a loading control. (C) qRT-PCR analysis of RBP2, c-myc, and PU.1 mRNA expression and the loading control β-actin in differentiated cells induced by ATRA. Data are mean ± SEM of 3 independent experiments. (D) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with ATRA. β-actin was a loading control. (E) The mRNA expression of RBP2, c-myc, and PU.1 in differentiated primary cells induced by DMSO. The results are from 3 independent experiments. *P< 0.05, **P< 0.01, ***P< 0.001.

Mentions: We determined the requirement for RBP2 in differentiation of leukemia cells by inducing granulocytic differentiation in vitro. RBP2 mRNA and protein levels were increased (Figure 1A-D) in K562 and HL60 cells undergoing granulocytic differentiation induced by DMSO or ATRA (Supplement Figure 1). As expected, the expression of differentiation-related c-myc and Notch1 was downregulated and PU.1 expression was upregulated after terminal differentiation (Figure 1A-D). In addition, CML-BP primary cells were treated with DMSO for 7 days, with similar results (Figure 1E). Therefore, RBP2 induces leukemia cell differentiation.


Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

Zhou M, Zeng J, Wang X, Wang X, Huang T, Fu Y, Sun T, Jia J, Chen C - Oncotarget (2015)

RBP2 induces cell differentiation(A) The mRNA expression of RBP2 in differentiated K562 and HL60 leukemia cells induced by DMSO. Quantitative RT-PCR (qRT-PCR) analysis of the mRNA levels of RBP2, c-myc, and PU.1 and loading control β-actin. Data are mean ± SEM of 3 independent experiments. (B) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with DMSO. β-actin was a loading control. (C) qRT-PCR analysis of RBP2, c-myc, and PU.1 mRNA expression and the loading control β-actin in differentiated cells induced by ATRA. Data are mean ± SEM of 3 independent experiments. (D) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with ATRA. β-actin was a loading control. (E) The mRNA expression of RBP2, c-myc, and PU.1 in differentiated primary cells induced by DMSO. The results are from 3 independent experiments. *P< 0.05, **P< 0.01, ***P< 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359230&req=5

Figure 1: RBP2 induces cell differentiation(A) The mRNA expression of RBP2 in differentiated K562 and HL60 leukemia cells induced by DMSO. Quantitative RT-PCR (qRT-PCR) analysis of the mRNA levels of RBP2, c-myc, and PU.1 and loading control β-actin. Data are mean ± SEM of 3 independent experiments. (B) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with DMSO. β-actin was a loading control. (C) qRT-PCR analysis of RBP2, c-myc, and PU.1 mRNA expression and the loading control β-actin in differentiated cells induced by ATRA. Data are mean ± SEM of 3 independent experiments. (D) Western blot analysis of RBP2, c-myc, PU.1 and Notch1 protein level after treatment with ATRA. β-actin was a loading control. (E) The mRNA expression of RBP2, c-myc, and PU.1 in differentiated primary cells induced by DMSO. The results are from 3 independent experiments. *P< 0.05, **P< 0.01, ***P< 0.001.
Mentions: We determined the requirement for RBP2 in differentiation of leukemia cells by inducing granulocytic differentiation in vitro. RBP2 mRNA and protein levels were increased (Figure 1A-D) in K562 and HL60 cells undergoing granulocytic differentiation induced by DMSO or ATRA (Supplement Figure 1). As expected, the expression of differentiation-related c-myc and Notch1 was downregulated and PU.1 expression was upregulated after terminal differentiation (Figure 1A-D). In addition, CML-BP primary cells were treated with DMSO for 7 days, with similar results (Figure 1E). Therefore, RBP2 induces leukemia cell differentiation.

Bottom Line: In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP.This in turn activated PDCD4.In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China.

ABSTRACT
Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

Show MeSH
Related in: MedlinePlus