Page 33 - Annual Report 2020

m6A methylation allows a set of proliferation/ anti-apoptotic genes to be rapidly turned on, thus helping a subpopulation of cells escape TKI- mediated killing. To test this, we modeled and characterized TKI resistance in different leukemia models, including chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML), and directly mapped m6A in the transcriptomes of leukemia cells. We showed that the heterogeneous FTO-m6A axis with the homogeneous RTK cells facilitates a subpopulation of cells to rapidly repro- gram their m6A methylome in order to upregulate survival and proliferation genes, so that they can withstand an initial onslaught of TKIs and continu- ously propagate in the absence of targeted kinase activities. On the other hand, the increased FTO-m6A functions by TKIs further enhance expression of anti-apoptotic/survival genes, ultimately leading to the establishment of resistant phenotypes. When the FTO-mediated m6A demethylation is either genetically or pharmacologically inhibited, the resis- tant cells regain partial sensitivity to TKIs. Further, our studies revealed that aberrant m6A methylation influences the outcomes of leukemia patients in response to epigenetic therapy. These findings are published in Blood.
Discover EZH1 as an essential regula- tor for AML1-ETO-positive leukemia
The AML1/ETO gene, resulting from t(8;21) translocation, encodes a chimeric protein
(AE) that is a leukemia-initiating transcrip-
tion factor in AML. While many AE+ AML
patients achieve complete remission rate,
and this subset of AML is often referred as
having a favorable prognosis, more than
40% AE+ patients die eventually with largely unknown reasons. Although observed less frequently, lysine methylation of non-histone proteins critically regulates their functions,
and contributes to tumorigenesis. Yet whether
AE is subjected to regulation by lysine methylation is unknown.
EZH1 is a histone lysine methyltransferase (PKMT) that has histone lysine residues as the only sub- strates. Our studies found that EZH1 expression
is higher in AE+ than AE negative (AE-) AML blasts and that high expression of EZH1, but not EZH2, predicts inferior outcomes in AE+ patients. EZH1 depletion in AE+ SKNO-1 cells induces growth arrest, and AE-EZH1 co-expression leads to a higher colony number compared to single gene. Mechanistic stud- ies revealed that EZH1 interacts with AE, and they are enriched in target promoters. While AE has >30 lysine residues, only lysine 43 (Lys43) can be meth- ylated (meK43), and EZH1 is likely responsible for Lys43 methylation. Loss of meK43 decreases colony number and inhibits AML cell growth in in vivo. These findings are published in Nature communications.
Overall, our discoveries offer new insights into the molecular biology of cancer pathogenesis and
drug resistance, identify new prognostic biomarkers and therapeutic targets, and develop novel thera- peutic reagents to improve the managment of cancerous lesions.
Publications:
1. DouL,YanF,PangJ,ZhengD,LiD,GaoL, Wang L, Xu Y, Shi J, Wang Q, Zhou L, Shen N,SinghP,WangL,LiY,GaoY,LiuT,Chen
C, Al-Kali A, Litzow M, Chi Y, Bode A, Liu C, Huang H, Liu D, Marcucci G, Liu S,* Yu L. Protein Lysine 43 Methylation by EZH1 Pro- motes AML1-ETO Transcriptional Repression in Leukemia. Nature Communications, 2019 Nov 7;10(1):5051. (*Corresponding Author and Lead Contact).
2. Liu X, Pang J, Seiler S, Kempen R, Liu H, Al-Kali A, Tretyakova N, Litzow M, Liu S. DNA Cytosine-Demethylating Agent 5-Aza-2’-Deoxycytidine Targets Leukemia Cells through Reducing DNA N6-Methyl- adenine. Blood, Volume 134, Issue Supple- ment_1, November 13, 2019.
THE HORMEL INSTITUTE // UNIVERSITY OF MINNESOTA PG 33