Publication Date:
2018-11-29
Description:
Transcriptional plasticity is an evolving phenomenon in cancer biology. Mutational profiling alone may not suffice to dissect transcriptional dependency and underlying epigenetic vulnerabilities in tumorigenesis. Histone 3 lysine 27 (H3K27) demethylases (UTX, UTY and JMJD3) critically regulate transcriptional architecture. Recently it has been demonstrated that Utx (Kdm6a) plays tumor suppressor role in myeloid leukemogenesis through noncatalytic activity (Gozdecka M, et al., Nat Genet, 2018). Conditional (Mx1-Cre) deletion of Utx caused development of acute myeloid leukemia (AML) in ~ 60% of the mice; wherein, only Utx-/-, but not Utx+/-, aged (22 months) mice presented with AML. Paradoxically, previous report suggested that Utx conditional (Vav1-Cre) knock out male/female mice did not develop leukemia over 18 months (Tian, L., et al., Blood, 2015). In our recent report we have identified that expression of UTX is significantly increased in human primary AML, and pharmacological inhibition of H3K27 demethylase catalytic activity attenuated survival of AML cells (Boila L.D. et al,. Exp Hematol, 2017). Therefore the contribution of UTX in AML pathogenesis remains context dependent, and probably contentious, and warrants further investigations. ATP-dependent chromatin remodelers have been implicated in AML pathobiology (Chatterjee S.S., et al., Mol Cancer Res, 2018). We reported that loss of MBD3, a scaffold of NuRD chromatin remodeler, in human primary AML cells associates with nucleation of leukemic NuRD (Biswas M et al., Blood, 2017). Loss of Mbd3(Vav1-Cre) has been shown to disrupt NuRD complex integrity and causes T-cell lymphoma, suggesting tissue-specific function of NuRD (Loughran, S.J., et al., J Exp Med, 2017). Interestingly, in our present study we have identified for the first time that endogenous UTX, but not JMJD3, reversibly co-immunoprecipitates with NuRD in AML cells. These findings led us to test the hypothesis whether UTX would participate with NuRD in AML. ChIP-seq analysis in AML blasts using antibodies against UTX and CHD4 (intact ATPase component of leukemic NuRD) along with H3K27ac identified the co-localized genes. ChIP-qPCR, transcriptome, pathway analysis (P
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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