Open AccessForced Expression of Cyclin-Dependent Kinase 6 Confers Resistance of Pro-B Acute Lymphocytic Leukemia to Gleevec Treatment
Author(s) -
Tracy C. Kuo,
Joseph Chavarría-Smith,
Dan Huang,
Mark S. Schlissel
Publication year - 2011
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01349-10
Subject(s) - biology , cyclin dependent kinase 6 , cancer research , abl , imatinib mesylate , chronic myelogenous leukemia , tyrosine kinase , pim1 , breakpoint cluster region , philadelphia chromosome , leukemia , kinase , signal transduction , microbiology and biotechnology , imatinib , cyclin dependent kinase 2 , chromosomal translocation , immunology , protein kinase a , gene , genetics , phosphorylation , myeloid leukemia , serine
The gene encoding c-ABL, a nonreceptor protein tyrosine kinase, is involved in a chromosomal translocation resulting in expression of a BCR-Abl fusion protein that causes most chronic myelogenous and some acute lymphocytic leukemias (CML and ALL) in humans. The Abelson murine leukemia virus (A-MuLV) expresses an alternative form of c-Abl, v-Abl, that transforms murine pro-B cells, resulting in acute leukemia and providing an experimental model for human disease. Gleevec (STI571) inhibits the Abl kinase and has shown great utility against CML and ALL in humans, although its usefulness is limited by acquired resistance. Since STI571 is active against A-MuLV-transformed cellsin vitro , we performed a retroviral cDNA library screen for genes that confer resistance to apoptosis induced by STI571. We found that forced expression ofCdk6 promotes continued cell division and decreased apoptosis of leukemic cells. We then determined that the transcription factor E2A negatively regulatesCdk6 transcription in leukemic pro-B cells and that the v-Abl kinase stimulatesCdk6 expression via an extracellular signal-regulated kinase 1-dependent pathway. Finally, we show that the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor PD0332991 can act synergistically with STI571 to enhance leukemic cell death, suggesting a potential role for CDK6 inhibitors in the treatment of STI571-resistant CML or ALL.