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.

New therapeutic approaches in myelodysplastic syndromes: Hypomethylating agents and lenalidomide

“…In keeping with this model, resistance to LEN has been shown to be associated with restoration of P53 accumulation, and ACCEPTED MANUSCRIPT inhibition of TP53 expression by an antisense oligonucleotide modestly enhances del(5q) erythropoiesis 126 . Finally, sub-clonal TP53 mutations are associated to lower rates of cytogenetic responses to LEN, though they do not influence the restoration of erythropoiesis 127 .…”

The molecular basis and clinical significance of genetic mutations identified in myelodysplastic syndromes

“…Note: *frequent mutation site. [58,121]. In Wu's study, U2AF1 mutation was found to be an independent poor-risk factor for OS in all patients (P = 0.030) and could predict a shorter time-to-leukemia transformation in younger patients (P = 0.020), particularly in lower-risk MDS patients [151].…”

“…Cenersen, an antisense oligonucleotide complementary to TP53, suppresses mutant p53 expression and restores impaired erythropoiesis in patients with del(5q) MDS [121].…”

Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

“…Suppression of p53 reduces apoptosis and restores erythropoiesis in del(5q) MDS progenitors. Specifically, dexamethasone, a glucocorticoid receptor‐dependent p53 antagonist, restored transfusion independence in 5 out of 8 del(5q) MDS patients with acquired drug resistance . Cenersen, a clinically active 20‐mer antisense oligonucleotide complementary to TP53 exon 10, is another treatment that has been shown to reduce apoptosis and restore erythropoiesis in RPS14 deficient erythroblasts by significantly reducing cellular p53 …”

“…Specifically, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, restored transfusion independence in 5 out of 8 del(5q) MDS patients with acquired drug resistance. 50 Cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon 10, is another treatment that has been shown to reduce apoptosis and restore erythropoiesis in RPS14 deficient erythroblasts by significantly reducing cellular p53. 50 The presence of a TP53 mutation has been associated with resistance to lenalidomide, as well as inferior prognosis compared to patients with wild-type TP53.…”