SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia

Publikation: Bidrag til tidsskrift › Kommentar/debat › Forskning › fagfællebedømt

Standard

SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia. / Yan, Dongqing; Franzini, Anca; Pomicter, Anthony D.; Halverson, Brayden J.; Antelope, Orlando; Mason, Clinton C.; Ahmann, Jonathan M.; Senina, Anna V.; Vellore, Nadeem A.; Jones, Courtney L.; Zabriskie, Matthew S.; Than, Hein; Xiao, Michael J.; van Scoyk, Alexandria; Patel, Ami B.; Clair, Phillip M.; Heaton, William L.; Owen, Shawn C.; Andersen, Joshua L.; Egbert, Christina M.; Reisz, Julie A.; D'Alessandro, Angelo; Cox, James E.; Gantz, Kevin C.; Redwine, Hannah M.; Iyer, Siddharth M.; Khorashad, Jamshid S.; Rajabi, Nima; Olsen, Christian A.; O'Hare, Thomas; Deininger, Michael W.

I: Cancer Discovery, Bind 2, Nr. 3, 2021, s. 266-287.

Publikation: Bidrag til tidsskrift › Kommentar/debat › Forskning › fagfællebedømt

Harvard

Yan, D, Franzini, A, Pomicter, AD, Halverson, BJ, Antelope, O, Mason, CC, Ahmann, JM, Senina, AV, Vellore, NA, Jones, CL, Zabriskie, MS, Than, H, Xiao, MJ, van Scoyk, A, Patel, AB, Clair, PM, Heaton, WL, Owen, SC, Andersen, JL, Egbert, CM, Reisz, JA, D'Alessandro, A, Cox, JE, Gantz, KC, Redwine, HM, Iyer, SM, Khorashad, JS, Rajabi, N, Olsen, CA, O'Hare, T & Deininger, MW 2021, 'SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia', Cancer Discovery, bind 2, nr. 3, s. 266-287. https://doi.org/10.1158/2643-3230.BCD-20-0168

APA

Yan, D., Franzini, A., Pomicter, A. D., Halverson, B. J., Antelope, O., Mason, C. C., Ahmann, J. M., Senina, A. V., Vellore, N. A., Jones, C. L., Zabriskie, M. S., Than, H., Xiao, M. J., van Scoyk, A., Patel, A. B., Clair, P. M., Heaton, W. L., Owen, S. C., Andersen, J. L., ... Deininger, M. W. (2021). SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia. Cancer Discovery, 2(3), 266-287. https://doi.org/10.1158/2643-3230.BCD-20-0168

Vancouver

Yan D, Franzini A, Pomicter AD, Halverson BJ, Antelope O, Mason CC o.a. SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia. Cancer Discovery. 2021;2(3):266-287. https://doi.org/10.1158/2643-3230.BCD-20-0168

Author

Yan, Dongqing ; Franzini, Anca ; Pomicter, Anthony D. ; Halverson, Brayden J. ; Antelope, Orlando ; Mason, Clinton C. ; Ahmann, Jonathan M. ; Senina, Anna V. ; Vellore, Nadeem A. ; Jones, Courtney L. ; Zabriskie, Matthew S. ; Than, Hein ; Xiao, Michael J. ; van Scoyk, Alexandria ; Patel, Ami B. ; Clair, Phillip M. ; Heaton, William L. ; Owen, Shawn C. ; Andersen, Joshua L. ; Egbert, Christina M. ; Reisz, Julie A. ; D'Alessandro, Angelo ; Cox, James E. ; Gantz, Kevin C. ; Redwine, Hannah M. ; Iyer, Siddharth M. ; Khorashad, Jamshid S. ; Rajabi, Nima ; Olsen, Christian A. ; O'Hare, Thomas ; Deininger, Michael W. / SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia. I: Cancer Discovery. 2021 ; Bind 2, Nr. 3. s. 266-287.

Bibtex

@article{a02d387dd7ca45a29021ccde09a34818,
title = "SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia",
abstract = "We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. SIGNIFICANCE: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML.See related commentary by Li and Melnick, p. 198.",
author = "Dongqing Yan and Anca Franzini and Pomicter, {Anthony D.} and Halverson, {Brayden J.} and Orlando Antelope and Mason, {Clinton C.} and Ahmann, {Jonathan M.} and Senina, {Anna V.} and Vellore, {Nadeem A.} and Jones, {Courtney L.} and Zabriskie, {Matthew S.} and Hein Than and Xiao, {Michael J.} and {van Scoyk}, Alexandria and Patel, {Ami B.} and Clair, {Phillip M.} and Heaton, {William L.} and Owen, {Shawn C.} and Andersen, {Joshua L.} and Egbert, {Christina M.} and Reisz, {Julie A.} and Angelo D'Alessandro and Cox, {James E.} and Gantz, {Kevin C.} and Redwine, {Hannah M.} and Iyer, {Siddharth M.} and Khorashad, {Jamshid S.} and Nima Rajabi and Olsen, {Christian A.} and Thomas O'Hare and Deininger, {Michael W.}",
note = "Publisher Copyright: {\textcopyright}2021 American Association for Cancer Research.",
year = "2021",
doi = "10.1158/2643-3230.BCD-20-0168",
language = "English",
volume = "2",
pages = "266--287",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research",
number = "3",

}

RIS

TY - JOUR

T1 - SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia

AU - Yan, Dongqing

AU - Franzini, Anca

AU - Pomicter, Anthony D.

AU - Halverson, Brayden J.

AU - Antelope, Orlando

AU - Mason, Clinton C.

AU - Ahmann, Jonathan M.

AU - Senina, Anna V.

AU - Vellore, Nadeem A.

AU - Jones, Courtney L.

AU - Zabriskie, Matthew S.

AU - Than, Hein

AU - Xiao, Michael J.

AU - van Scoyk, Alexandria

AU - Patel, Ami B.

AU - Clair, Phillip M.

AU - Heaton, William L.

AU - Owen, Shawn C.

AU - Andersen, Joshua L.

AU - Egbert, Christina M.

AU - Reisz, Julie A.

AU - D'Alessandro, Angelo

AU - Cox, James E.

AU - Gantz, Kevin C.

AU - Redwine, Hannah M.

AU - Iyer, Siddharth M.

AU - Khorashad, Jamshid S.

AU - Rajabi, Nima

AU - Olsen, Christian A.

AU - O'Hare, Thomas

AU - Deininger, Michael W.

N1 - Publisher Copyright: ©2021 American Association for Cancer Research.

PY - 2021

Y1 - 2021

N2 - We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. SIGNIFICANCE: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML.See related commentary by Li and Melnick, p. 198.

AB - We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. SIGNIFICANCE: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML.See related commentary by Li and Melnick, p. 198.

U2 - 10.1158/2643-3230.BCD-20-0168

DO - 10.1158/2643-3230.BCD-20-0168

M3 - Comment/debate

C2 - 34027418

AN - SCOPUS:85110992902

VL - 2

SP - 266

EP - 287

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 3

ER -

ID: 286502646