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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2075-2083. Prepublished online as a Blood First Edition Paper on May 30, 2007; DOI 10.1182/blood-2007-02-071266. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-02-071266v1 110/6/2075    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, L. Articles by Briesewitz, R. Search for Related Content PubMed PubMed Citation Articles by Wang, L. Articles by Briesewitz, R. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia Lisheng Wang1, Jie Wang1, Bradley W. Blaser2, Anne-Marie Duchemin4, Donna F. Kusewitt3, Tom Liu5, Michael A. Caligiuri2,5, and Roger Briesewitz1,5 1 Department of Pharmacology, 2 Department of Internal Medicine and the Integrated Biomedical Science Graduate Program, 3 Department of Veterinary Biosciences, 4 Department of Psychiatry, and 5 The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus Entry into the cell cycle is mediated by cyclin-dependent kinase 4/6 (CDK4/6) activation, followed by CDK2 activation. We found that pharmacologic inhibition of the Flt3 internal tandem duplication (ITD), a mutated receptor tyrosine kinase commonly found in patients with acute myelogenous leukemia (AML), led to the down-regulation of cyclin D2 and D3 followed by retinoblastoma protein (pRb) dephosphorylation and G1 cell-cycle arrest. This implicated the D-cyclin-CDK4/6 complex as a downstream effector of Flt3 ITD signaling. Indeed, single-agent PD0332991, a selective CDK4/6 inhibitor, caused sustained cell-cycle arrest in Flt3 ITD AML cell lines and prolonged survival in an in vivo model of Flt3 ITD AML. PD0332991 caused an initial cell-cycle arrest in well-established Flt3 wild-type (wt) AML cell lines, but this was overcome by down-regulation of p27Kip and reactivation of CDK2. This acquired resistance was not observed in a Flt3 ITD and a Flt3 wt sample from a patient with primary AML. In summary, the mechanism of cell-cycle arrest after treatment of Flt3 ITD AML with a Flt3 inhibitor involves down-regulation of cyclin D2 and D3. As such, CDK4/6 can be a therapeutic target in Flt3 ITD AML but also in primary Flt3 wt AML. Finally, acquired resistance to CDK4/6 inhibition can arise through activation CDK2. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Menu, J. Garcia, X. Huang, M. Di Liberto, P. L. Toogood, I. Chen, K. Vanderkerken, and S. Chen-Kiang A Novel Therapeutic Combination Using PD 0332991 and Bortezomib: Study in the 5T33MM Myeloma Model Cancer Res., July 15, 2008; 68(14): 5519 - 5523. [Abstract] [Full Text] [PDF]

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