Lenalidomide promotes p53 degradation by inhibiting MDM2 auto-ubiquitination in myelodysplastic syndrome with chromosome 5q deletion

Abstract

Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion [del(5q)]. Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of MDM2, with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that lenalidomide inhibits the haplodeficient PP2Acα phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS-14 to suppress MDM2 auto-ubiquitination; whereas PP2Acα over expression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to lenalidomide over-expressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that lenalidomide restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.

TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

“…In inherited disorders of ribosomal insufficiency such as Diamond-Blackfan anemia, corticosteroids remain the cornerstone of treatment to improve erythropoiesis. We previously reported that p53 expression is up-regulated in del (5q) erythroid precursors upon the development of resistance to lenalidomide treatment (11). We reasoned that the addition of dexamethasone may suppress p53 in vivo, thereby restoring lenalidomide responsiveness.…”

“…Paraffin-embedded bone marrow biopsy sections (4 μm thick) from lenalidomide-resistant MDS patients were evaluated for p53 and spectrin expression before and after combined treatment with lenalidomide and dexamethasone, as previously described (11). For details, see SI Materials and Methods.…”

“…We recently reported that lenalidomide promotes p53 degradation by stabilizing MDM2, thereby fostering cell cycle reentry and subsequent G2/M arrest of del(5q) progenitors by inhibiting two haplo-deficient phosphatases: protein phosphatase 2A catalytic domain alpha and cell division cycle 25C (10). Treatment with lenalidomide significantly reduced p53 expression in bone marrow erythroid precursors of responding del(5q) MDS patients; however, on emergence of drug resistance, p53 accumulation was restored (11). Although responses to lenalidomide are relatively durable, 50% of patients acquire resistance to lenalidomide within 2-3 y (2).…”

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes

“…[4][5][6] Lenalidomide is used primarily in lower-risk patients with the del(5q) cytogenetic abnormality and purportedly works by selectively suppressing del(5q) clones by inhibiting haplodeficient phosphatases encoded within or near the proximal common deleted region that serves to release progenitors from p53 arrest followed by terminal arrest and apoptosis at G 2 /M, in association with a defect in ribosomal protein function. [7][8][9] In patients without this lesion, lenalidomide has multiple effects that range from modulation of the bone marrow microenvironment, inhibition of lysine demethylase, and potentiation of erythropoietin signaling. [10][11][12] Lenalidomide has demonstrated transfusionindependence response rates of 67% in lower-risk, transfusiondependent del(5q) patients with MDS; 26% in lower-risk patients without del(5q); and 14% and 30% in older patients with acute myeloid leukemia (AML) with or without the del(5q) abnormality, respectively.…”

Established and novel agents for myelodysplastic syndromes

“…Its activity is thought to be mediated through selective suppression of del(5q) clones by inhibition of haplodeficient phosphatases encoded within or near the proximal common deleted region that releases progenitors from p53 arrest, followed by terminal arrest and apoptosis at G 2 /M, in association with a defect in ribosomal protein function. 18,19 In non-del(5q) anemia MDS patients, lenalidomide likely modulates the BM microenvironment, inhibits lysine demethylase, and potentiates erythropoietin signaling.…”