Disease-stabilizing treatment based on all-trans retinoic acid and valproic acid in acute myeloid leukemia – identification of responders by gene expression profiling of pretreatment leukemic cells

BMC Cancer

Research Article

Sigrid Erdal¹  Randi Hovland¹  Håkon Reikvam²  Bjørn Tore Gjertsen³  Hanne Fredly³  Øystein Bruserud³  Rakel Brendsdal Forthun³ 

[1] Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway;Department of Medicine, Haukeland University Hospital, N-5021, Bergen, Norway;Section for Hematology, Institute of Clinical Science, University of Bergen, Bergen, Norway;

关键词: Acute myeloid leukemia;    All-trans retinoic acid;    Valproic acid;    Gene expression profiling;   

DOI  :  10.1186/s12885-017-3620-y

 received in 2016-07-18, accepted in 2017-08-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundAcute myeloid leukemia (AML) is an aggressive malignancy only cured by intensive therapy. However, many elderly and unfit patients cannot receive such treatment due to an unacceptable risk of treatment-related morbidity and mortality. Disease-stabilizing therapy is then the only possible strategy, one alternative being treatment based on all-trans retinoic acid (ATRA) combined with the histone deacetylase inhibitor valproic acid and possibly low-toxicity conventional chemotherapy.MethodsPrimary AML cells were derived from 43 patients included in two clinical studies of treatment based on ATRA, valproic acid and theophyllamine; low toxicity chemotherapy (low-dose cytarabine, hydroxyurea, 6-mercaptopurin) was also allowed. Pretreatment leukemic cells were analyzed by mutation profiling of 54 genes frequently mutated in myeloid malignancies and by global gene expression profiling before and during in vivo treatment.ResultsPatients were classified as responders and non-responders to the treatment, however response to treatment showed no significant associations with karyotype or mutational profiles. Significance analysis of microarray (SAM) showed that responders and non-responders significantly differed with regard to the expression of 179 different genes. The differentially expressed genes encoding proteins with a known function were further classified based on the PANTHER (protein annotation through evolutionary relationship) classification system. The identified genes encoded proteins that are involved in several important biological functions, but a main subset of the genes were important for transcriptional regulation. These pretherapy differences in gene expression were largely maintained during treatment. Our analyses of primary AML cells during in vivo treatment suggest that ATRA modulates HOX activity (i.e. decreased expression of HOXA3, HOXA4 and HOXA5 and their regulator PBX3), but altered function of DNA methyl transferase 3A (DNMT3A) and G-protein coupled receptor signaling may also contribute to the effect of the overall treatment.ConclusionsResponders and non-responders to AML stabilizing treatment based on ATRA and valproic acid differ in the pretreatment transcriptional regulation of their leukemic cells, and these differences may be important for the clinical effect of this treatment.Trial registrationsClinicalTrials.gov no. NCT00175812; EudraCT no. 2004–001663-22, registered September 9, 2005 and ClinicalTrials.gov no. NCT00995332; EudraCT no. 2007–2007–001995-36, registered October 14, 2009.

【 授权许可】

CC BY   
© The Author(s). 2017