title: Correlation of clinical response and response duration with miR-145 induction by lenalidomide in CD34(+) cells from patients with del(5q) myelodysplastic syndrome.
abstract: We examined whether lenalidomide exposure up-regulates miRNAs and mRNAs, previously shown to play a role in the disease phenotype of del(5q) myelodysplastic syndrome, in pre-treatment CD34(+) marrow cells. We hypothesized that increased expression would predict for clinical response. Changes in miR-143, miR-145, miR-146a, miR-146b, miR-378, miR-584, SPARC and RPS14 were examined in del(5q) (n=10) and non-del(5q) (n=18) myelodysplastic syndrome patient samples. Significantly increased expression of miR-143 (1.8-fold and 1.5-fold in del(5q) and non-del(5q), respectively), and miR-145 (1.9-fold and 1.6-fold in del(5q) and non-del(5q), respectively) was observed. In the del(5q) myelodysplastic syndrome cohort, transfusion independence correlated with a 1.3-fold or more increase in miR-145 expression and response over 12 months correlated with a 1.5-fold or more increase. Knockdown of miR-143 and miR-145 in cord blood CD34(+) cells resulted in increased erythroid progenitor activity. Lenalidomide selectively abrogated progenitor activity in cells depleted of miR-143 and miR-145 supporting a key role for miR-143/145 in the sensitivity to lenalidomide of del(5q) myelodysplastic syndrome patients.
authors.affiliation: Leukemia/Bone Marrow Transplant Program, Division of Hematology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Venner
authors.forename: Joanna Wegrzyn
authors.initials: JW
authors.lastname: Woltosz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nevill
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.forename: Gisela
authors.initials: G
authors.lastname: Caceres
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.forename: Bart L
authors.initials: BL
authors.lastname: Scott
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Sandy
authors.initials: S
authors.lastname: Sung
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D000077269:Lenalidomide; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D013792:Thalidomide; D000077269:Lenalidomide