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

Ralf Buettner, Le Xuan Truong Nguyen, Bijender Kumar, Corey Morales, Chao Liu, Lisa S Chen, Tea Pemovska, Timothy W. Synold, Joycelynne Palmer, Ryan Thompson, Ling Li, Dinh Hoa Hoang, Bin Zhang, Lucy Ghoda, Claudia Kowolik, Mika Kontro, Calum Leitch, Krister Wennerberg, Xiaochun Yu, Ching Cheng Chen & 5 others David Horne, Varsha V Gandhi, Vinod Pullarkat, Guido Marcucci, Steven T. Rosen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)16295-16303
Number of pages9
JournalJournal of Cellular Physiology
Volume234
Issue number9
DOIs
StatePublished - Sep 1 2019

Fingerprint

Acute Myeloid Leukemia
Adenosine
Stem cells
Stem Cells
Myeloid Cells
RNA
Nucleosides
Leukemia
Mutation
Chemotherapy
Ribose
Survival
DNA
Proliferating Cell Nuclear Antigen
Cell proliferation
Transcription
Protein-Tyrosine Kinases
DNA Damage
Carrier Proteins
Cells

Keywords

  • FLT3
  • RNA
  • acute myeloid leukemia
  • antileukemic
  • apoptosis
  • nucleoside

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Buettner, R., Nguyen, L. X. T., Kumar, B., Morales, C., Liu, C., Chen, L. S., ... Rosen, S. T. (2019). 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia. Journal of Cellular Physiology, 234(9), 16295-16303. https://doi.org/10.1002/jcp.28294

8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia. / Buettner, Ralf; Nguyen, Le Xuan Truong; Kumar, Bijender; Morales, Corey; Liu, Chao; Chen, Lisa S; Pemovska, Tea; Synold, Timothy W.; Palmer, Joycelynne; Thompson, Ryan; Li, Ling; Hoang, Dinh Hoa; Zhang, Bin; Ghoda, Lucy; Kowolik, Claudia; Kontro, Mika; Leitch, Calum; Wennerberg, Krister; Yu, Xiaochun; Chen, Ching Cheng; Horne, David; Gandhi, Varsha V; Pullarkat, Vinod; Marcucci, Guido; Rosen, Steven T.

In: Journal of Cellular Physiology, Vol. 234, No. 9, 01.09.2019, p. 16295-16303.

Research output: Contribution to journalArticle

Buettner, R, Nguyen, LXT, Kumar, B, Morales, C, Liu, C, Chen, LS, Pemovska, T, Synold, TW, Palmer, J, Thompson, R, Li, L, Hoang, DH, Zhang, B, Ghoda, L, Kowolik, C, Kontro, M, Leitch, C, Wennerberg, K, Yu, X, Chen, CC, Horne, D, Gandhi, VV, Pullarkat, V, Marcucci, G & Rosen, ST 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
Buettner R, Nguyen LXT, Kumar B, Morales C, Liu C, Chen LS et al. 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia. Journal of Cellular Physiology. 2019 Sep 1;234(9):16295-16303. https://doi.org/10.1002/jcp.28294
Buettner, Ralf ; Nguyen, Le Xuan Truong ; Kumar, Bijender ; Morales, Corey ; Liu, Chao ; Chen, Lisa S ; Pemovska, Tea ; Synold, Timothy W. ; Palmer, Joycelynne ; Thompson, Ryan ; Li, Ling ; Hoang, Dinh Hoa ; Zhang, Bin ; Ghoda, Lucy ; Kowolik, Claudia ; Kontro, Mika ; Leitch, Calum ; Wennerberg, Krister ; Yu, Xiaochun ; Chen, Ching Cheng ; Horne, David ; Gandhi, Varsha V ; Pullarkat, Vinod ; Marcucci, Guido ; Rosen, Steven T. / 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia. In: Journal of Cellular Physiology. 2019 ; Vol. 234, No. 9. pp. 16295-16303.
@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 Gandhi, {Varsha V} and Vinod Pullarkat and Guido Marcucci and Rosen, {Steven T.}",
year = "2019",
month = "9",
day = "1",
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",

}

TY - JOUR

T1 - 8-chloro-adenosine activity in FLT3-ITD acute myeloid leukemia

AU - Buettner, Ralf

AU - Nguyen, Le Xuan Truong

AU - Kumar, Bijender

AU - Morales, Corey

AU - Liu, Chao

AU - Chen, Lisa S

AU - Pemovska, Tea

AU - Synold, Timothy W.

AU - Palmer, Joycelynne

AU - Thompson, Ryan

AU - Li, Ling

AU - Hoang, Dinh Hoa

AU - Zhang, Bin

AU - Ghoda, Lucy

AU - Kowolik, Claudia

AU - Kontro, Mika

AU - Leitch, Calum

AU - Wennerberg, Krister

AU - Yu, Xiaochun

AU - Chen, Ching Cheng

AU - Horne, David

AU - Gandhi, Varsha V

AU - Pullarkat, Vinod

AU - Marcucci, Guido

AU - Rosen, Steven T.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - FLT3

KW - RNA

KW - acute myeloid leukemia

KW - antileukemic

KW - apoptosis

KW - nucleoside

UR - http://www.scopus.com/inward/record.url?scp=85061619618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061619618&partnerID=8YFLogxK

U2 - 10.1002/jcp.28294

DO - 10.1002/jcp.28294

M3 - Article

VL - 234

SP - 16295

EP - 16303

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 9

ER -