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J Cell Physiol. 2019 Feb 15. doi: 10.1002/jcp.28294. [Epub ahead of print]

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

Author information

1
Hematology Malignancies and Stem Cell Transplantation Institute, Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, California.
2
Department of Medical Biotechnology, Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City, Vietnam.
3
Department of Cancer Genetics and Epigenetics, City of Hope National Medical Center, Duarte, California.
4
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
6
Department of Cancer Biology, City of Hope National Medical Center, Duarte, California.
7
Department of Information Sciences, City of Hope National Medical Center, Duarte, California.
8
Department of Molecular Medicine, City of Hope National Medical Center, Duarte, California.
9
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
10
Department of Clinical Science, Center for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway.

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

PMID:
30770553
PMCID:
PMC6697246
[Available on 2020-08-15]
DOI:
10.1002/jcp.28294

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