Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

Nadine Hein, Donald P. Cameron, Katherine M Hannan, Nhu Y.N. Nguyen, Chun Yew Fong, Jirawas Sornkom, Meaghan Wall, Megan Pavy, Carleen M Cullinane, Jeannine Diesch, Jennifer R Devlin, Amee J. George, Elaine Sanij, Jaclyn E Quin, Gretchen Poortinga, Inge Verbrugge, Adele Baker, Denis J Drygin, Simon James Harrison, James D. Rozario & 10 others Jason A Powell, Stuart M Pitson, Johannes Zuber, Ricky W Johnstone, Mark A Dawson, Mark A. Guthridge, Andrew Wei, Grant A McArthur, Richard B. Pearson, Ross D. Hannan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of thisnewclass of inhibitors to treat highly aggressive AML by targeting LICs.

Original languageEnglish
Pages (from-to)2882-2895
Number of pages14
JournalBlood
Volume129
Issue number21
DOIs
Publication statusPublished - 25 May 2017

Cite this

Hein, Nadine ; Cameron, Donald P. ; Hannan, Katherine M ; Nguyen, Nhu Y.N. ; Fong, Chun Yew ; Sornkom, Jirawas ; Wall, Meaghan ; Pavy, Megan ; Cullinane, Carleen M ; Diesch, Jeannine ; Devlin, Jennifer R ; George, Amee J. ; Sanij, Elaine ; Quin, Jaclyn E ; Poortinga, Gretchen ; Verbrugge, Inge ; Baker, Adele ; Drygin, Denis J ; Harrison, Simon James ; Rozario, James D. ; Powell, Jason A ; Pitson, Stuart M ; Zuber, Johannes ; Johnstone, Ricky W ; Dawson, Mark A ; Guthridge, Mark A. ; Wei, Andrew ; McArthur, Grant A ; Pearson, Richard B. ; Hannan, Ross D. / Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. In: Blood. 2017 ; Vol. 129, No. 21. pp. 2882-2895.
@article{68bbfabda4c146aab8d0ac605a859c30,
title = "Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population",
abstract = "Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of thisnewclass of inhibitors to treat highly aggressive AML by targeting LICs.",
author = "Nadine Hein and Cameron, {Donald P.} and Hannan, {Katherine M} and Nguyen, {Nhu Y.N.} and Fong, {Chun Yew} and Jirawas Sornkom and Meaghan Wall and Megan Pavy and Cullinane, {Carleen M} and Jeannine Diesch and Devlin, {Jennifer R} and George, {Amee J.} and Elaine Sanij and Quin, {Jaclyn E} and Gretchen Poortinga and Inge Verbrugge and Adele Baker and Drygin, {Denis J} and Harrison, {Simon James} and Rozario, {James D.} and Powell, {Jason A} and Pitson, {Stuart M} and Johannes Zuber and Johnstone, {Ricky W} and Dawson, {Mark A} and Guthridge, {Mark A.} and Andrew Wei and McArthur, {Grant A} and Pearson, {Richard B.} and Hannan, {Ross D.}",
year = "2017",
month = "5",
day = "25",
doi = "10.1182/blood-2016-05-718171",
language = "English",
volume = "129",
pages = "2882--2895",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "21",

}

Hein, N, Cameron, DP, Hannan, KM, Nguyen, NYN, Fong, CY, Sornkom, J, Wall, M, Pavy, M, Cullinane, CM, Diesch, J, Devlin, JR, George, AJ, Sanij, E, Quin, JE, Poortinga, G, Verbrugge, I, Baker, A, Drygin, DJ, Harrison, SJ, Rozario, JD, Powell, JA, Pitson, SM, Zuber, J, Johnstone, RW, Dawson, MA, Guthridge, MA, Wei, A, McArthur, GA, Pearson, RB & Hannan, RD 2017, 'Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population', Blood, vol. 129, no. 21, pp. 2882-2895. https://doi.org/10.1182/blood-2016-05-718171

Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. / Hein, Nadine; Cameron, Donald P.; Hannan, Katherine M; Nguyen, Nhu Y.N.; Fong, Chun Yew; Sornkom, Jirawas; Wall, Meaghan; Pavy, Megan; Cullinane, Carleen M; Diesch, Jeannine; Devlin, Jennifer R; George, Amee J.; Sanij, Elaine; Quin, Jaclyn E; Poortinga, Gretchen; Verbrugge, Inge; Baker, Adele; Drygin, Denis J; Harrison, Simon James; Rozario, James D.; Powell, Jason A; Pitson, Stuart M; Zuber, Johannes; Johnstone, Ricky W; Dawson, Mark A; Guthridge, Mark A.; Wei, Andrew; McArthur, Grant A; Pearson, Richard B.; Hannan, Ross D.

In: Blood, Vol. 129, No. 21, 25.05.2017, p. 2882-2895.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population

AU - Hein, Nadine

AU - Cameron, Donald P.

AU - Hannan, Katherine M

AU - Nguyen, Nhu Y.N.

AU - Fong, Chun Yew

AU - Sornkom, Jirawas

AU - Wall, Meaghan

AU - Pavy, Megan

AU - Cullinane, Carleen M

AU - Diesch, Jeannine

AU - Devlin, Jennifer R

AU - George, Amee J.

AU - Sanij, Elaine

AU - Quin, Jaclyn E

AU - Poortinga, Gretchen

AU - Verbrugge, Inge

AU - Baker, Adele

AU - Drygin, Denis J

AU - Harrison, Simon James

AU - Rozario, James D.

AU - Powell, Jason A

AU - Pitson, Stuart M

AU - Zuber, Johannes

AU - Johnstone, Ricky W

AU - Dawson, Mark A

AU - Guthridge, Mark A.

AU - Wei, Andrew

AU - McArthur, Grant A

AU - Pearson, Richard B.

AU - Hannan, Ross D.

PY - 2017/5/25

Y1 - 2017/5/25

N2 - Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of thisnewclass of inhibitors to treat highly aggressive AML by targeting LICs.

AB - Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of thisnewclass of inhibitors to treat highly aggressive AML by targeting LICs.

UR - http://www.scopus.com/inward/record.url?scp=85019716272&partnerID=8YFLogxK

U2 - 10.1182/blood-2016-05-718171

DO - 10.1182/blood-2016-05-718171

M3 - Article

VL - 129

SP - 2882

EP - 2895

JO - Blood

JF - Blood

SN - 0006-4971

IS - 21

ER -