@article{03c632ca171f41ef8e61de918adf124f,
title = "8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia",
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.",
keywords = "FLT3, RNA, acute myeloid leukemia, antileukemic, apoptosis, nucleoside",
author = "Ralf Buettner and Nguyen, {Le Xuan Truong} and Bijender Kumar and Corey Morales and Chao Liu and Chen, {Lisa S.} and Tea Pemovska and Synold, {Timothy W.} and Joycelynne Palmer and Ryan Thompson and Ling Li and Hoang, {Dinh Hoa} and Bin Zhang and Lucy Ghoda and Claudia Kowolik and Mika Kontro and Calum Leitch and Krister Wennerberg and Xiaochun Yu and Chen, {Ching Cheng} and David Horne and Varsha Gandhi and Vinod Pullarkat and Guido Marcucci and Rosen, {Steven T.}",
note = "Funding Information: This project was supported by the Analytical Pharmacology Funding Information: This project was supported by the Analytical Pharmacology (Dr. Timothy Synold) and Small Animal Imaging (Dr. Jun Wu) Core Facilities at City of Hope supported by the National Cancer Institute under award number P30CA033572; the Helsinki/Bergen AML individualized systems medicine team (Drs. Tero Aittokallio, Bj?rn Tore Gjertsen, Caroline Heckman, Olli Kallioniemi, Kimmo Porkka, Krister Wennerberg) and the FIMM High Throughput Biomedicine, Information Technology and Sequencing units. The study was also in part supported by the National Cancer Institute grant R01CA201496 and the Rising Tide Foundation for Clinical Cancer Research (RTFCCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors like to thank James Sanchez (City of Hope) for editorial support. Funding Information: National Cancer Institute, Grant/Award Numbers: P30CA033572, R01CA201496; Rising Tide Foundation for Clinical Cancer Research Funding Information: Facilities at City of Hope supported by the National Cancer Institute under award number P30CA033572; the Helsinki/ Bergen AML individualized systems medicine team (Drs. Tero Aittokallio, Bj{\o}rn Tore Gjertsen, Caroline Heckman, Olli Kallioniemi, Kimmo Porkka, Krister Wennerberg) and the FIMM High Throughput Biomedicine, Information Technology and Sequencing units. The study was also in part supported by the National Cancer Institute grant R01CA201496 and the Rising Tide Foundation for Clinical Cancer Research (RTFCCR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors like to thank James Sanchez (City of Hope) for editorial support. Publisher Copyright: {\textcopyright} 2019 Wiley Periodicals, Inc.",
year = "2019",
month = sep,
doi = "10.1002/jcp.28294",
language = "English (US)",
volume = "234",
pages = "16295--16303",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "9",
}