Abstract
The cAMP signalling pathway has emerged as a key regulator of haematopoietic cell proliferation, differentiation and apoptosis. In parallel, general understanding of the biology of cyclic nucleotide PDEs (phosphodiesterases) has advanced considerably, revealing the remarkable complexity of this enzyme system that regulates the amplitude, kinetics and location of intracellular cAMP-mediated signalling. The development of therapeutic inhibitors of specific PDE gene families has resulted in a growing appreciation of the potential therapeutic application of PDE inhibitors to the treatment of immune-mediated illnesses and haematopoietic malignancies. This review summarizes the expression and function of PDEs in normal haematopoietic cells and the evidence that family-specific inhibitors will be therapeutically useful in myeloid and lymphoid malignancies.
Highlights
Following the identification of cAMP in 1958 by Rall and Sutherland [1], research focused for more than a decade on elucidating the role that this ‘second messenger’ played in regulating metabolic pathways, as well as identifying the enzymes responsible for cAMP synthesis and catabolism [1,2,3]
As at least one of these compounds, 16-oxoestradiol, induced maturation of acute myeloid leukaemia (AML) blast cells from a patient with M1 AML, a subtype that is not all-trans-retinoic acid (ATRA)-responsive, this study suggested that activation of cAMP signalling pathways may help to drive differentiation in AML subtypes for which differentiative therapies have not yet been identified [205]
A growing literature suggests that combined inhibition of multiple cyclic nucleotide phosphodiesterase (PDE) families may be more efficacious than targeted therapy of a single PDE family. In keeping with these observations, we found that inhibition of PDE4 in B-chronic lymphocytic leukaemia (CLL) cells in vitro led to augmented levels of PDE3B by Western blot analysis, presumably as part of a compensatory feedback loop in response to increased cAMP signalling induced by the PDE4 inhibitor [96]
Summary
Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies Adam LERNER*† and Paul M. The cAMP signalling pathway has emerged as a key regulator of haematopoietic cell proliferation, differentiation and apoptosis. General understanding of the biology of cyclic nucleotide PDEs (phosphodiesterases) has advanced considerably, revealing the remarkable complexity of this enzyme system that regulates the amplitude, kinetics and location of intracellular cAMPmediated signalling. The development of therapeutic inhibitors of specific PDE gene families has resulted in a growing appreciation of the potential therapeutic application of PDE inhibitors to the treatment of immune-mediated illnesses and haematopoietic malignancies. This review summarizes the expression and function of PDEs in normal haematopoietic cells and the evidence that family-specific inhibitors will be therapeutically useful in myeloid and lymphoid malignancies
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