Home LiteratureArticle Details
PMID: 16997913 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 40 ·2006-10-03 ·Pages 14907-12

Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC, Kimura S, Ottmann OG, Druker BJ, Villunger A, Roberts AW, Strasser A

Abstract

Cell killing is a critical pharmacological activity of imatinib to eradicate Bcr/Abl+ leukemias. We found that imatinib kills Bcr/Abl+ leukemic cells by triggering the Bcl-2-regulated apoptotic pathway. Imatinib activated several proapoptotic BH3-only proteins: bim and bmf transcription was increased, and both Bim and Bad were activated posttranslationally. Studies using RNAi and cells from gene-targeted mice revealed that Bim plays a major role in imatinib-induced apoptosis of Bcr/Abl+ leukemic cells and that the combined loss of Bim and Bad abrogates this killing. Loss of Bmf or Puma had no effect. Resistance to imatinib caused by Bcl-2 overexpression or loss of Bim (plus Bad) could be overcome by cotreatment with the BH3 mimetic ABT-737. These results demonstrate that Bim and Bad account for most, perhaps all, imatinib-induced killing of Bcr/Abl+ leukemic cells and suggest previously undescribed drug combination strategies for cancer therapy.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Apoptosis/drug effects Apoptosis Regulatory Proteins/genetics,metabolism Bcl-2-Like Protein 11 Benzamides Biphenyl Compounds/pharmacology Cell Line, Tumor Cell Transformation, Neoplastic Cytotoxicity, Immunologic/drug effects Drug Resistance, Neoplasm Fetus/cytology Fusion Proteins, bcr-abl Humans Imatinib Mesylate Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology Liver/cytology Membrane Proteins/genetics,metabolism Mice Myeloid Progenitor Cells/cytology Nitrophenols Piperazines/pharmacology Protein-Tyrosine Kinases/metabolism Proto-Oncogene Proteins/genetics,metabolism Proto-Oncogene Proteins c-bcl-2/metabolism Pyrimidines/pharmacology Sulfonamides bcl-Associated Death Protein/metabolism
Chemicals
ABT-737 Antineoplastic Agents Apoptosis Regulatory Proteins BCL2L11 protein, human Bcl-2-Like Protein 11 Bcl2l11 protein, mouse Benzamides Biphenyl Compounds Membrane Proteins Nitrophenols Piperazines Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Pyrimidines Sulfonamides bcl-Associated Death Protein Imatinib Mesylate Protein-Tyrosine Kinases Fusion Proteins, bcr-abl
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kuroda Junya
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Puthalakath Hamsa
Cragg Mark S
Kelly Priscilla N
Bouillet Philippe
Huang David C S
Kimura Shinya
Ottmann Oliver G
Druker Brian J
Villunger Andreas
Roberts Andrew W
Strasser Andreas
References (26)
26 references, click to expand
  1. Bad-deficient mice develop diffuse large B cell lymphoma.
    Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9324-9 PMID: 12876200
  2. An inhibitor of Bcl-2 family proteins induces regression of solid tumours.
    Nature. 2005 Jun 2;435(7042):677-81 PMID: 15902208
  3. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity.
    Science. 1999 Nov 26;286(5445):1735-8 PMID: 10576740
  4. Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-x(L).
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14871-6 PMID: 10611305
  5. Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival.
    Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14943-8 PMID: 10611317
  6. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL.
    J Exp Med. 2000 Mar 20;191(6):977-84 PMID: 10727459
  7. Apoptosis signaling.
    Annu Rev Biochem. 2000;69:217-45 PMID: 10966458
  8. BH3-Only proteins-essential initiators of apoptotic cell death.
    Cell. 2000 Dec 8;103(6):839-42 PMID: 11136969
  9. Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis.
    Science. 2001 Sep 7;293(5536):1829-32 PMID: 11546872
  10. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins.
    Cell Death Differ. 2002 May;9(5):505-12 PMID: 11973609
  11. A member of Forkhead transcription factor FKHRL1 is a downstream effector of STI571-induced cell cycle arrest in BCR-ABL-expressing cells.
    J Biol Chem. 2003 Feb 21;278(8):6411-9 PMID: 12456669
  12. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim.
    J Biol Chem. 2003 May 23;278(21):18811-6 PMID: 12646560
  13. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment.
    Blood. 2003 Jun 15;101(12):4701-7 PMID: 12576334
  14. Polycystic kidney disease prevented by transgenic RNA interference.
    Cell Death Differ. 2005 Jul;12(7):831-3 PMID: 15818405
  15. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate.
    Blood. 2003 Sep 15;102(6):2229-35 PMID: 12763930
  16. Phosphorylation of Bim-EL by Erk1/2 on serine 69 promotes its degradation via the proteasome pathway and regulates its proapoptotic function.
    Oncogene. 2003 Oct 2;22(43):6785-93 PMID: 14555991
  17. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways.
    Cancer Cell. 2003 Oct;4(4):321-8 PMID: 14585359
  18. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa.
    Science. 2003 Nov 7;302(5647):1036-8 PMID: 14500851
  19. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro.
    Blood. 2003 Dec 15;102(13):4499-503 PMID: 12881321
  20. Regulation of osteoclast apoptosis by ubiquitylation of proapoptotic BH3-only Bcl-2 family member Bim.
    EMBO J. 2003 Dec 15;22(24):6653-64 PMID: 14657036
  21. Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors.
    Mol Cell Biol. 2004 Jul;24(14):6172-83 PMID: 15226421
  22. The pathophysiology of mitochondrial cell death.
    Science. 2004 Jul 30;305(5684):626-9 PMID: 15286356
  23. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines.
    Blood. 1996 Aug 1;88(3):809-16 PMID: 8704235
  24. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)
    Cell. 1996 Nov 15;87(4):619-28 PMID: 8929531
  25. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.
    Mol Cell. 2005 Feb 4;17(3):393-403 PMID: 15694340
  26. The development of imatinib as a therapeutic agent for chronic myeloid leukemia.
    Blood. 2005 Apr 1;105(7):2640-53 PMID: 15618470
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0606176103
Published
2006-10-03
Epub
2006-00-22
Pages
14907-12
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1595449
Subset
IM
Grants
NCI NIH HHS · R01 CA043540 · United States
NCI NIH HHS · R01 CA080188 · United States
NCI NIH HHS · CA 43540 · United States
NCI NIH HHS · CA 80188 · United States
Corrections
ErratumIn
-
CommentIn
PMID: 17003111
External Links
PubMed source DOI: 10.1073/pnas.0606176103 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2