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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,458
RHO GTPASES: Biochemistry and Biology
Jaffe, A. B., & Hall, A. (2005) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.020604.150721 · Cited by 3,009
Burridge, K., & Wennerberg, K. (2004) · Cell · doi:10.1016/s0092-8674(04)00003-0 · Cited by 1,578
Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9
Krivtsov, A. V., Twomey, D., Feng, Z., Stubbs, M. C., Wang, Y., Faber, J., Levine, J. E., Wang, J., Hahn, W. C., Gilliland, D. G., et al. (2006) · Nature · doi:10.1038/nature04980 · Cited by 1,513
Konopleva, M. Y., Contractor, R., Tsao, T., Samudio, I. J., Ruvolo, P. P., Kitada, S., Deng, X., Zhai, D., Shi, Y.-X., Sneed, T. B., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.10.006 · Cited by 1,046
Programmed Anuclear Cell Death Delimits Platelet Life Span
Mason, K. D., Carpinelli, M. R., Fletcher, J. I., Collinge, J. E., Hilton, A. A., Ellis, S., Kelly, P. N., Ekert, P. G., Metcalf, D., Roberts, A. W., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.037 · Cited by 1,031
Gandhi, L., Camidge, D. R., Ribeiro de Oliveira, M., Bonomi, P., Gandara, D., Khaira, D., Hann, C. L., McKeegan, E. M., Litvinovich, E., Hemken, P. M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.6208 · Cited by 603
Lin, C., Smith, E. R., Takahashi, H., Lai, K. C., Martin‐Brown, S., Florens, L. A., Washburn, M. P., Conaway, J. W., Conaway, R., & Shilatifard, A. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.01.026 · Cited by 594
Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia
Somervaille, T. C. P., & Cleary, M. L. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.020 · Cited by 582
Systems biology and combination therapy in the quest for clinical efficacy
Fitzgerald, J. B., Schoeberl, B., Nielsen, U. B., & Sorger, P. K. (2006) · Nature Chemical Biology · doi:10.1038/nchembio817 · Cited by 570
Cited by
Rho GTPase signaling in cancer progression and dissemination
Crosas‐Molist, E., Samain, R., Kohlhammer, L., Orgaz, J. L., George, S. L., Maiques, Ó., Barcelo, J., & Sanz‐Moreno, V. (2021) · Physiological Reviews · doi:10.1152/physrev.00045.2020 · Cited by 300
The Rac GTPase in Cancer: From Old Concepts to New Paradigms
Kazanietz, M. G., & Caloca, M. J. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1456 · Cited by 199
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Goyama, S., Schibler, J., Cunningham, L., Zhang, Y., Rao, Y., Nishimoto, N., Nakagawa, M. M., Olsson, A., Wunderlich, M., Link, K. A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68557 · Cited by 197
Self-citationRho GTPases: Anti- or pro-neoplastic targets?
Zandvakili, I., Lin, Y., Morris, J. C., & Zheng, Y. (2016) · Oncogene · doi:10.1038/onc.2016.473 · Cited by 104
Self-citationFunctions of BCL-X L at the Interface between Cell Death and Metabolism
Michels, J., Kepp, O., Senovilla, L., Lissa, D., Castedo, M., Kroemer, G., & Galluzzi, L. (2013) · International Journal of Cell Biology · doi:10.1155/2013/705294 · Cited by 101
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
