Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease

Emily K. Thomas, Jose A. Cancelas, Hee Don Chae, Adrienne D. Cox, Patricia J. Keller, Danilo Perrotti, Paolo Neviani, Brian Druker, Kenneth D R Setchell, Yi Zheng, Chad E. Harris, David A. Williams

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

Original languageEnglish (US)
Pages (from-to)467-478
Number of pages12
JournalCancer Cell
Volume12
Issue number5
DOIs
StatePublished - Nov 13 2007

Fingerprint

Guanosine
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Therapeutics
Gene Targeting
Heterografts
Animal Models
Phenotype
Proteins

Keywords

  • CELLCYCLE

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Thomas, E. K., Cancelas, J. A., Chae, H. D., Cox, A. D., Keller, P. J., Perrotti, D., ... Williams, D. A. (2007). Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease. Cancer Cell, 12(5), 467-478. https://doi.org/10.1016/j.ccr.2007.10.015

Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease. / Thomas, Emily K.; Cancelas, Jose A.; Chae, Hee Don; Cox, Adrienne D.; Keller, Patricia J.; Perrotti, Danilo; Neviani, Paolo; Druker, Brian; Setchell, Kenneth D R; Zheng, Yi; Harris, Chad E.; Williams, David A.

In: Cancer Cell, Vol. 12, No. 5, 13.11.2007, p. 467-478.

Research output: Contribution to journalArticle

Thomas, EK, Cancelas, JA, Chae, HD, Cox, AD, Keller, PJ, Perrotti, D, Neviani, P, Druker, B, Setchell, KDR, Zheng, Y, Harris, CE & Williams, DA 2007, 'Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease', Cancer Cell, vol. 12, no. 5, pp. 467-478. https://doi.org/10.1016/j.ccr.2007.10.015
Thomas, Emily K. ; Cancelas, Jose A. ; Chae, Hee Don ; Cox, Adrienne D. ; Keller, Patricia J. ; Perrotti, Danilo ; Neviani, Paolo ; Druker, Brian ; Setchell, Kenneth D R ; Zheng, Yi ; Harris, Chad E. ; Williams, David A. / Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease. In: Cancer Cell. 2007 ; Vol. 12, No. 5. pp. 467-478.
@article{5ca8909f21734351a93fa254708f8f7e,
title = "Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease",
abstract = "Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.",
keywords = "CELLCYCLE",
author = "Thomas, {Emily K.} and Cancelas, {Jose A.} and Chae, {Hee Don} and Cox, {Adrienne D.} and Keller, {Patricia J.} and Danilo Perrotti and Paolo Neviani and Brian Druker and Setchell, {Kenneth D R} and Yi Zheng and Harris, {Chad E.} and Williams, {David A.}",
year = "2007",
month = "11",
day = "13",
doi = "10.1016/j.ccr.2007.10.015",
language = "English (US)",
volume = "12",
pages = "467--478",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Rac Guanosine Triphosphatases Represent Integrating Molecular Therapeutic Targets for BCR-ABL-Induced Myeloproliferative Disease

AU - Thomas, Emily K.

AU - Cancelas, Jose A.

AU - Chae, Hee Don

AU - Cox, Adrienne D.

AU - Keller, Patricia J.

AU - Perrotti, Danilo

AU - Neviani, Paolo

AU - Druker, Brian

AU - Setchell, Kenneth D R

AU - Zheng, Yi

AU - Harris, Chad E.

AU - Williams, David A.

PY - 2007/11/13

Y1 - 2007/11/13

N2 - Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

AB - Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

KW - CELLCYCLE

UR - http://www.scopus.com/inward/record.url?scp=35748943189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35748943189&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2007.10.015

DO - 10.1016/j.ccr.2007.10.015

M3 - Article

C2 - 17996650

AN - SCOPUS:35748943189

VL - 12

SP - 467

EP - 478

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -