8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia

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Buettner , R , Le Xuan Truong Nguyen , Kumar , B , Morales , C , Liu , C , Chen , L S , Pemovska , T , Synold , T W , Palmer , J , Thompson , R , Li , L , Dinh Hoa Hoang , Zhang , B , Ghoda , L , Kowolik , C , Kontro , M , Leitch , C , Wennerberg , K , Yu , X , Chen , C-C , Horne , D , Gandhi , V , Pullarkat , V , Marcucci , G & Rosen , S T 2019 , ' 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia ' , Journal of Cellular Physiology , vol. 234 , no. 9 , pp. 16295-16303 . https://doi.org/10.1002/jcp.28294

Title: 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia
Author: Buettner, Ralf; Le Xuan Truong Nguyen,; Kumar, Bijender; Morales, Corey; Liu, Chao; Chen, Lisa S.; Pemovska, Tea; Synold, Timothy W.; Palmer, Joycelynne; Thompson, Ryan; Li, Ling; Dinh Hoa Hoang,; Zhang, Bin; Ghoda, Lucy; Kowolik, Claudia; Kontro, Mika; Leitch, Calum; Wennerberg, Krister; Yu, Xiaochun; Chen, Ching-Cheng; Horne, David; Gandhi, Varsha; Pullarkat, Vinod; Marcucci, Guido; Rosen, Steven T.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Oncology
University of Helsinki, Krister Wennerberg / Principal Investigator
Date: 2019-09
Language: eng
Number of pages: 9
Belongs to series: Journal of Cellular Physiology
ISSN: 0021-9541
URI: http://hdl.handle.net/10138/312899
Abstract: Nucleoside analogs represent the backbone of several distinct chemotherapy regimens for acute myeloid leukemia (AML) and combination with tyrosine kinase inhibitors has improved survival of AML patients, including those harboring the poor-risk FLT3-ITD mutation. Although these compounds are effective in killing proliferating blasts, they lack activity against quiescent leukemia stem cells (LSCs), which contributes to initial treatment refractoriness or subsequent disease relapse. The reagent 8-chloro-adenosine (8-Cl-Ado) is a ribose-containing, RNA-directed nucleoside analog that is incorporated into newly transcribed RNA rather than in DNA, causing inhibition of RNA transcription. In this report, we demonstrate antileukemic activities of 8-Cl-Ado in vitro and in vivo and provide mechanistic insight into the mode of action of 8-Cl-Ado in AML. 8-Cl-Ado markedly induced apoptosis in LSC, with negligible effects on normal stem cells. 8-Cl-Ado was particularly effective against AML cell lines and primary AML blast cells harboring the FLT3-ITD mutation. FLT3-ITD is associated with high expression of miR-155. Furthermore, we demonstrate that 8-Cl-Ado inhibits miR-155 expression levels accompanied by induction of DNA-damage and suppression of cell proliferation, through regulation of miR-155/ErbB3 binding protein 1(Ebp1)/p53/PCNA signaling. Finally, we determined that combined treatment of NSG mice engrafted with FLT3-ITD (+) MV4-11 AML cells with 8-Cl-Ado and the FLT3 inhibitor AC220 (quizartinib) synergistically enhanced survival, compared with that of mice treated with the individual drugs, suggesting a potentially effective approach for FLT3-ITD AML patients.
Subject: acute myeloid leukemia
antileukemic
apoptosis
FLT3
nucleoside
RNA
INHIBITION
NUCLEOSIDE
EXPRESSION
ANALOGS
CANCER
CELLS
OLDER
GENE
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
3122 Cancers
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