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2015 ; 3
(ä): 16
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Targeting cell cycle regulators in hematologic malignancies
#MMPMID25914884
Aleem E
; Arceci RJ
Front Cell Dev Biol
2015[]; 3
(ä): 16
PMID25914884
show ga
Hematologic malignancies represent the fourth most frequently diagnosed cancer in
economically developed countries. In hematologic malignancies normal
hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem
or progenitor cell (HSPC) that maintains its ability of self-renewal.
Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but
also influence other vital cellular processes, such as stem cell renewal,
differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair.
Chromosomal translocations, amplification, overexpression and altered CDK
activities have been described in different types of human cancer, which have
made them attractive targets for pharmacological inhibition. Mouse models
deficient for one or more CDKs have significantly contributed to our current
understanding of the physiological functions of CDKs, as well as their roles in
human cancer. The present review focuses on selected cell cycle kinases with
recent emerging key functions in hematopoiesis and in hematopoietic malignancies,
such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic
leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and
cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge
gained from gene knockout experiments in mice of these kinases is also
summarized. An overview of compounds targeting these kinases, which are currently
in clinical development in various solid tumors and hematopoietic malignances, is
presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011,
LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol,
AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase
inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors
with conventional chemotherapeutic agents used in the treatment of AML, such as
cytarabine, is discussed.