Cyclic AMP can promote APL progression and protect myeloid leukemia cells against anthracycline-induced apoptosis

G Gausdal,S O Døskeland,F Schwede,R Kleppe,M Lanotte,N Rouhee,F Pendino,L Herfindal,E Nguyen,U Havemann,E Ségal-Bendirdjian,Ø Bruserud,A Wergeland,B T Gjertsen,J Skavland,E Mccormack

doi:10.1038/cddis.2013.39

Abstract

We show that cyclic AMP (cAMP) elevating agents protect blasts from patients with acute promyelocytic leukemia (APL) against death induced by first-line anti-leukemic anthracyclines like daunorubicin (DNR). The cAMP effect was reproduced in NB4 APL cells, and shown to depend on activation of the generally cytoplasmic cAMP-kinase type I (PKA-I) rather than the perinuclear PKA-II. The protection of both NB4 cells and APL blasts was associated with (inactivating) phosphorylation of PKA site Ser118 of pro-apoptotic Bad and (activating) phosphorylation of PKA site Ser133 of the AML oncogene CREB. Either event would be expected to protect broadly against cell death, and we found cAMP elevation to protect also against 2-deoxyglucose, rotenone, proteasome inhibitor and a BH3-only mimetic. The in vitro findings were mirrored by the findings in NSG mice with orthotopic NB4 cell leukemia. The mice showed more rapid disease progression when given cAMP-increasing agents (prostaglandin E2 analog and theophylline), both with and without DNR chemotherapy. The all-trans retinoic acid (ATRA)-induced terminal APL cell differentiation is a cornerstone in current APL treatment and is enhanced by cAMP. We show also that ATRA-resistant APL cells, believed to be responsible for treatment failure with current ATRA-based treatment protocols, were protected by cAMP against death. This suggests that the beneficial pro-differentiating and non-beneficial pro-survival APL cell effects of cAMP should be weighed against each other. The results suggest also general awareness toward drugs that can affect bone marrow cAMP levels in leukemia patients.

Highlights

CAMP concentration can be increased by phosphodiesterase (PDE)-inhibiting drugs
The findings indicate awareness when patients on Cyclic AMP (cAMP)-elevating agents like theophylline are treated with anthracyclines, or when cAMP stimulation is considered combined with all-trans retinoic acid (ATRA) to boost acute promyelocytic leukemia (APL) cell differentiation
We found that human NB4 cells, widely accepted as being representative of human APL,[5] were strongly protected by cAMP agonists against death induced by the first-line anti-leukemic anthracycline drug DNR

Summary

Introduction

CAMP concentration can be increased by phosphodiesterase (PDE)-inhibiting drugs. Stimulation of cAMP signaling by PDE inhibitor enhanced the effect of ATRA on survival of syngenic PML-RARA APL mice and mice transplanted with NB4 cells,[6,7,8] and retarded the APL progression in a patient.[7] cAMP stimulation protects mature neutrophils[9,10,11] and promonocytic leukemia cells[12] against death and induces death of the BNML-derived AML line IPC,[13] little is known about the impact of cAMP on APL cell survival This is of particular concern as ATRA is used together with an anthracycline (daunorubicin; DNR or idarubicin; IDA) in current APL treatment protocols.[14,15]. The findings indicate awareness when patients on cAMP-elevating agents like theophylline are treated with anthracyclines, or when cAMP stimulation is considered combined with ATRA to boost APL cell differentiation

Methods

Results

Conclusion