EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia

Abstract ObjectiveMyelodysplastic syndrome (MDS) is a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells and may develop to acute myeloid leukemia (AML). We investigated the mechanism of histone methyltransferases EZH2/EHMT2 during the transformation of MDS to AML.MethodsExpression of EZH2/EHMT2 in MDS/AML patients and in NHD13 mice was detected. EZH2 and EHMT2 were silenced or overexpressed in SKM-1 cells to evaluate cell proliferation and cycle. Levels of DLX5, H3K27me3 and H3K9me2 were detected. The binding of DLX5 promoter region to H3K27me3 and H3K9me2 was examined. Levels of H3K27me3/H3K9me2 in cells were decreased by EZH2/EHMT2 inhibitors, and then changes of DLX5 expression and cell proliferation were observed.ResultsEZH2 was poorly expressed in MDS patients but highly expressed in MDS-AML patients. EHMT2 was elevated in both MDS and MDS-AML patients. EZH2 expression was reduced and EHMT2 expression was promoted in NHD13 mice. NHD13 mice with overexpressing EZH2 or EHMT2 transformed into AML more quickly. Intervention of EZH2 or EHMT2 inhibited SKM-1 cell proliferation and promoted DLX5 expression. Both silencing EZH1 and EZH2 in SKM-1 cells, the H3K27me3 level was decreased. EZH2 silencing repressed the proliferation of SKM-1 cells. The transcription level of DLX5 in SKM-1 cells was inhibited by H3K27me3 and H3K9me2. Enhanced DLX5 expression restrained the proliferation of SKM-1 cells.ConclusionEZH2/EHMT2 catalyzed H3K27me3/H3K9me2 to inhibit the transcription of DLX5, thus promoting the transformation from MDS to AML.

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EZH2/EHMT2 Histone Methyltransferases Inhibit the Transcription of DLX5 and Promote the Transformation of Myelodysplastic Syndrome to Acute Myeloid Leukemia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.619795 ◽

2021 ◽

Vol 9 ◽

Author(s):

Zhuanzhen Zheng ◽

Ling Li ◽

Guoxia Li ◽

Yaofang Zhang ◽

Chunxia Dong ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Transcription Level ◽

Histone Methyltransferases ◽

Clonal Hematopoiesis ◽

H3k27me3 Level ◽

Ezh2 Expression ◽

Acute Myeloid

Myelodysplastic syndrome (MDS) is characterized by clonal hematopoiesis and impaired differentiation, and may develop to acute myeloid leukemia (AML). We explored the mechanism of histone methyltransferase EZH2/EHMT2 during the transformation of MDS into AML. Expression of EZH2/EHMT2 in patients and NHD13 mice was detected. EZH2 and EHMT2 were silenced or overexpressed in SKM-1 cells. The cell proliferation and cycle were evaluated. Levels of DLX5, H3K27me3, and H3K9me2 in SKM-1 cells were detected. Binding of DLX5 promoter region to H3K27me3 and H3K9me2 was examined. Levels of H3K27me3/H3K9me2 were decreased by EZH2/EHMT2 inhibitor (EPZ-6438/BIX-01294), and changes of DLX5 expression and cell proliferation were observed. EZH2 was poorly expressed in MDS patients but highly expressed in MDS-AML patients. EHMT2 was promoted in both MDS and MDS-AML patients. EZH2 expression was reduced and EHMT2 expression was promoted in NHD13 mice. NHD13 mice with overexpressing EZH2 or EHMT2 transformed into AML more quickly. Intervention of EZH2 or EHMT2 inhibited SKM-1 cell proliferation and promoted DLX5 expression. When silencing EZH1 and EZH2 in SKM-1 cells, the H3K27me3 level was decreased. EZH2 silencing repressed the proliferation of SKM-1 cells. Transcription level of DLX5 in SKM-1 cells was inhibited by H3K27me3 and H3K9me2. Enhanced DLX5 repressed SKM-1 cell proliferation. In conclusion, EZH2/EHMT2 catalyzed H3K27me3/H3K9me2 to inhibit the transcription of DLX5, thus promoting the transformation from MDS to AML.

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Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment

Blood ◽

10.1182/blood-2013-01-480129 ◽

2013 ◽

Vol 122 (5) ◽

pp. 749-758 ◽

Cited By ~ 124

Author(s):

Francis Mussai ◽

Carmela De Santo ◽

Issa Abu-Dayyeh ◽

Sarah Booth ◽

Lynn Quek ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Myeloid Leukemia ◽

T Cell Proliferation ◽

Hematopoietic Stem ◽

Key Points ◽

Immunosuppressive Microenvironment ◽

Acute Myeloid

Key Points AML blasts have an arginase-dependent ability to inhibit T-cell proliferation and hematopoietic stem cells. AML blasts have an arginase-dependent ability to modulate the polarization of monocytes.

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The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis.

Haematologica ◽

10.3324/haematol.2020.254987 ◽

2020 ◽

pp. 0-0

Author(s):

Bauke De Boer ◽

Sofia Sheveleva ◽

Katja Apelt ◽

Edo Vellenga ◽

Andre B. Mulder ◽

...

Keyword(s):

Bone Marrow ◽

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Bone Marrow Niche ◽

Hematopoietic Stem ◽

Signaling Axis ◽

Plasma Membrane Receptor ◽

Colony Forming Capacity ◽

Acute Myeloid

Upregulation of the plasma membrane receptor IL1RAP in Acute Myeloid Leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMP-like state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1β resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFκB signaling pathways in IL1RAP-expressing AML cells, but IL1β-induced signaling was dispensable for AML cell proliferation and NFκB-driven survival. IL1RAP was also expressed in stromal cells where IL1β induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1β-induced inflammatory secretome of IL1RAPexpressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an FDA-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy.

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PRL2 Maintains Hematopoietic Stem and Progenitor Cells Through Regulating SCF/KIT Signaling

Blood ◽

10.1182/blood.v122.21.3674.3674 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3674-3674

Author(s):

Michihiro Kobayashi ◽

Yuanshu Dong ◽

Hao Yu ◽

Yunpeng Bai ◽

Sisi Chen ◽

...

Keyword(s):

Cell Proliferation ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Progenitor Cell ◽

Conflicts Of Interest ◽

Critical Role ◽

Hematopoietic Progenitor Cell ◽

Hematopoietic Stem ◽

Acute Myeloid

Abstract The phosphatase of regenerating liver family of phosphatases, consisting of PRL1, PRL2 and PRL3, represents an intriguing group of proteins implicated in cell proliferation and tumorigenesis. However, the role of PRLs in normal and malignant hematopoiesis is largely unknown. While SCF/KIT signaling plays an important role in hematopoietic stem and progenitor cell (HSPC) maintenance, how SCF/KIT signaling is regulated in HSPCs remains poorly understood. We here report that PRL2 regulates HSPC maintenance through regulating SCF/KIT signaling. To define the role of PRL2 in hematopoiesis, we analyzed the hematopoietic stem cell (HSC) behavior in Prl2 deficient mice generated by our group. Prl2 deficiency results in ineffective hematopoiesis and impairs the long-term repopulating ability of HSCs. In addition, Prl2 null HSPCs are less proliferative and show decreased colony formation in response to SCF stimulation. Furthermore, Prl2 null HSPCs show reduced activation of the PI3K/AKT and ERK signaling in steady state and following SCF stimulation. Importantly, we found that PRL2 associates with KIT and the ability of PRL2 to enhance SCF signaling depends on its enzymatic activity, demonstrating that PRL2 mediates SCF/KIT signaling in HSPCs. Thus, PRL2 plays a critical role in hematopoietic stem and progenitor cell maintenance through regulating SCF/KIT signaling. Furthermore, loss of Prl2 decreased the ability of oncogenic KITD814V mutant in promoting hematopoietic progenitor cell proliferation and in activation of signaling pathways. We also checked the expression of PRL2 proteins in human AML cell lines and found increased level of PRL2 proteins in some acute myeloid leukemia (AML) cells compared with normal human bone marrow cells, indicating that PRL2 may play a pathological role in AML. Our results suggest that the PRL2 phosphatase may be a druggable target in myeloproliferative disease (MPD) and acute myeloid leukemia (AML) with oncogenic KIT mutations. Disclosures: No relevant conflicts of interest to declare.

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