title: High level of full-length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide.
abstract: Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug lenalidomide and poor survival outcomes in multiple myeloma (MM) patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study, we evaluate cereblon expression in mononuclear cells isolated from bone marrow [23 lower risk MDS patients with isolated 5q deletion (5q-), 37 lower risk MDS patients with chromosome 5 without the deletion of long arms (non-5q-), and 24 healthy controls] and from peripheral blood (38 patients with 5q-, 52 non-5q- patients and 25 healthy controls) to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion and, secondly, into the mechanisms of lenalidomide action. Patients with 5q- lower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS without the deletion of long arms of chromosome 5 and healthy controls. CRBN gene expression was measured using the quantitative TaqMan real-time PCR. High levels of CRBN mRNA were detected in all lenalidomide responders during the course of therapy. A significant decrease of the CRBN mRNA level during lenalidomide treatment is associated with loss of response to treatment and disease progression. These results suggest that, similar to the treatment of MM, high levels of full-length CRBN mRNA in lower risk 5q- patients are necessary for the efficacy of lenalidomide.
authors.affiliation: 1st Medical Clinic, General University Hospital Prague, Prague, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonasova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.|Faculty of Science, Charles University, Prague, Czech Republic.
authors.forename: Radka
authors.initials: R
authors.lastname: Bokorova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Polak
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Vostry
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Arnost
authors.initials: A
authors.lastname: Kostecka
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hajkova
authors.affiliation: 1st Medical Clinic, General University Hospital Prague, Prague, Czech Republic.
authors.forename: Radana
authors.initials: R
authors.lastname: Neuwirtova
authors.affiliation: 1st Medical Clinic, General University Hospital Prague, Prague, Czech Republic.
authors.forename: Magda
authors.initials: M
authors.lastname: Siskova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Sponerova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Cermak
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Mikulenkova
authors.affiliation: Leukemic Group, Faculty Hospital, Brno, Czech Republic.
authors.forename: Libor
authors.initials: L
authors.lastname: Cervinek
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Brezinova
authors.affiliation: Center of Oncocytogenetics, General University Hospital, Prague, Czech Republic.
authors.forename: Kyra
authors.initials: K
authors.lastname: Michalova
authors.affiliation: Institute of Hematology and Blood Transfusion, Prague, Czech Republic.
authors.forename: Ota
authors.initials: O
authors.lastname: Fuchs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000748:Anemia, Macrocytic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D000077269:Lenalidomide; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D007155:Immunologic Factors; D012333:RNA, Messenger; D013792:Thalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide
keywords: cereblon mRNA; immunomodulatory drugs; myelodysplastic syndrome; myelodysplastic syndrome with isolated del(5q); quantitative polymerase chain reaction