title: TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients.
abstract: Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = -0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
authors.forename: Gisela
authors.initials: G
authors.lastname: Caceres
authors.forename: Kathy
authors.initials: K
authors.lastname: McGraw
authors.forename: Bon Ham
authors.initials: BH
authors.lastname: Yip
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Kenian
authors.initials: K
authors.lastname: Liu
authors.forename: Lan Min
authors.initials: LM
authors.lastname: Zhang
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Najla H
authors.initials: NH
authors.lastname: Al Ali
authors.forename: Ashley
authors.initials: A
authors.lastname: Basiorka
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Smith
authors.forename: F Joseph
authors.initials: FJ
authors.lastname: Daugherty
authors.forename: Neil
authors.initials: N
authors.lastname: Littleton
authors.forename: Richard A
authors.initials: RA
authors.lastname: Wells
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Rami S
authors.initials: RS
authors.lastname: Komrokji
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
mesh_terms: D001483:Base Sequence; D003907:Dexamethasone; D004351:Drug Resistance / Q000502:physiology; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D000077269:Lenalidomide; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D013792:Thalidomide / Q000031:analogs & derivatives; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D009841:Oligonucleotides; D016159:Tumor Suppressor Protein p53; D013792:Thalidomide; D003907:Dexamethasone; C570305:cenersen; D000077269:Lenalidomide
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