The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Inhibition of Rac GTPase signaling and downstream prosurvival Bcl-2 proteins as combination targeted therapy in MLL-AF9 leukemia
Open accessAbstract
The Rac family of small Rho GTPases coordinates diverse cellular functions in hematopoietic cells including adhesion, migration, cytoskeleton rearrangements, gene transcription, proliferation, and survival. The integrity of Rac signaling has also been found to critically regulate cellular functions in the initiation and maintenance of hematopoietic malignancies. Using an in vivo gene targeting approach, we demonstrate that Rac2, but not Rac1, is critical to the initiation of acute myeloid leukemia in a retroviral expression model of MLL-AF9 leukemogenesis. However, loss of either Rac1 or Rac2 is sufficient to impair survival and growth of the transformed MLL-AF9 leukemia. Rac2 is known to positively regulate expression of Bcl-2 family proteins toward a prosurvival balance. We demonstrate that disruption of downstream survival signaling through antiapoptotic Bcl-2 proteins is implicated in mediating the effects of Rac2 deficiency in MLL-AF9 leukemia. Indeed, overexpression of Bcl-xL is able to rescue the effects of Rac2 deficiency and MLL-AF9 cells are exquisitely sensitive to direct inhibition of Bcl-2 family proteins by the BH3-mimetic, ABT-737. Furthermore, concurrent exposure to NSC23766, a small-molecule inhibitor of Rac activation, increases the apoptotic effect of ABT-737, indicating the Rac/Bcl-2 survival pathway may be targeted synergistically.
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“inhibition of RAC activity has been proven a successful strategy to target primary human AML and CML cells in vitro and in vivo [29,32,33].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [29]
In the citing paper
“RAC activity has been implicated in the disease initiation and maintenance in various murine leukemia models, including BCR-ABL and MLL-AF9-driven transformation [29–32].”
From Mitochondrial Dysfunction in Human Leukemic Stem/Progenitor Cells upon Loss of RAC2 (2015) · cites this paper as [29]
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Metadata
- Authors
- Mizukawa, B., Wei, J., Shrestha, M., Wunderlich, M., Chou, F.-S., Griesinger, A., Harris, C. E., Kumar, A. R., Zheng, Y., Williams, D. A., & Mulloy, J. C.
- Affiliations
- Divisions of Oncology and
- Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
- Cincinnati Children's Hospital Medical Center (US)
- Boston Children's Hospital (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-11-10
- Volume
- 118
- Issue
- 19
- Pages
- 5235-5245
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3217406
- OpenAlex
- W2008350123
- Semantic Scholar
- 96aadae74e64c4db4f74b143b9d22835641692f4
- Cited by
- 70
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 2 · 2018: 9 · 2017: 5 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 12 · 2012: 7
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Funders
- National Cancer Institute (K08-CA12291, R01CA140518)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK062757, P30DK090971)
- National Center for Research Resources (M01RR008084)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD000850)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Keywords
- MLL-AF9 leukemia, Rac2, Rac1, Bcl-2 family proteins, Bcl-xL, survival signaling, acute myeloid leukemia, ABT-737, BH3 mimetics, NSC23766, Rac inhibitor, apoptosis, combination targeted therapy, leukemogenesis
- MeSH terms
- RAC2 GTP-Binding Protein, Aminoquinolines, Animals, Biphenyl Compounds, Humans, Mice, Inbred C57BL, Mice, Transgenic, Neuropeptides, Nitrophenols, Piperazines, Pyrimidines, Sulfonamides, Transplantation, Heterologous, Signal Transduction, Leukemia, Biphenotypic, Acute, Gene Expression, Mice, SCID, Mice, Inbred NOD, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, rac GTP-Binding Proteins, rac1 GTP-Binding Protein, Cell Line, Tumor, bcl-X Protein, Mice, Gene Knockdown Techniques
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