Implications of <em><em>TP53</em></em> Gene Mutations in Myelodysplastic Syndromes: A Review

Special Article - Anemia

J Blood Disord. 2015;2(2): 1028.

Implications of TP53 Gene Mutations in Myelodysplastic Syndromes: A Review

Gamez S, Ali A and Raza A*

Myelodysplastic Syndromes Center, Columbia University, USA

*Corresponding author: Raza A, Myelodysplastic Syndromes Center, Columbia University Medical Center, Columbia University in the City of New York, Milstein Hospital Building, 6N-435, 177 Fort Washington Avenue, New York, NY 10032 USA

Received: June 24, 2015; Accepted: July 30, 2015; Published: August 05, 2015


TP53 is a tumor suppressor gene that has come to be known as the Guardian of the Genome. Mutations in this tumor suppressor are found in at least half of all cancers. P53 plays a role in arresting the cell cycle and inducing apoptosis; it can be activated through a variety of means such as genotoxic stress, dysfunctional telomeres, oncogenic signaling, abnormal microtubules, ribosome biogenesis, and a variety of other modes. TP53 mutations are less frequently found in myelodysplastic syndromes; however, knowledge of TP53 mutations can more accurately predict a patient’s outcome. In general, mutations in TP53 correlate to a poor outcome and higher incidence of transformation to acute myeloid leukemia in patients with isolated del5q or a complex karyotype.

Keywords: Myelodysplastic syndromes; TP53; Acute myeloid leukemia; 5q- Syndrome; Tumor suppressors; Genetic mutations


TP53: Tumor Protein 53; MDS: Myelodysplastic Syndromes; AML: Acute Myeloid Leukemia; MDM2: Mouse Double Minute 2; ATM: Ataxia Telangiectasia-mutated; ATR: ATM-Rad3-related; PI3K: Phosphoinositide 3-kinase; MRN: MRE11-Rad50-Nbs1; CHK: Check Point Kinase 2; CDK: Cyclin-dependent Kinase; MPF: Maturation-promoting Factor; CDC2: Cell Division Cell 2; CDC25C: Cell Division Cell 25 C; Rb: Retinoblastoma Protein; TRF2: Telomere Repeat-binding Factor 2; ARF: Alternate Reading Frame; P14ARF: Alternate Reading Frame Protein 14; Myc: Avian Myelocytomatosis Viral Oncogene Homolog; Ras: Rat Sarcoma Viral Oncogene Homolog; RPL11: Ribosomal Protein L11; RPL23: Ribosomal Protein L23; RPL5: Ribosomal Protein L5; RPS7: Ribosomal Protein S7; AMPK: AMP-activated Protein Kinase; TSC2: Tuberous Sclerosis 2; mTOR: Mammalian Target of Rapamycin; NF-Y: Nuclear Transcription Factor Y; p300: E1A Binding Protein p300; EGR1: Early Growth Response 1; p63: Tumor Protein 63; p73: Tumor Protein 73; Sp1: Specificity Protein 1; ANKRD11: Ankyrin Repeat Domain 11 gene; VDR: Vitamin D Receptor; SMAD2: SMAD Family Member 2; NRD1: Nardilysin (N-Arginine Dibasic Convertase); EFEMP2: EGF-containing Fibulin-like Extracellular Matrix Protein 2; TOP1: Topoisomerase 1; BTG2: B-cell Translocation Gene 2; MRE11: Meiotic Recombination 11; t-MDS: Therapy Related MDS; HSCT: Hematopoietic Stem Cell Transplant; NRAS: Neuroblastoma RAS; RUNX1: Runt-related Transcription Factor 1; MLL: Mixed-Lineage Leukemia; IPSS: International Prognostic Scoring System; IPSS-R: International Prognostic Scoring System Revised; SF3B1: Splicing Factor 3b Subunit 1; TET2: Tet Methylcytosine Dioxygenase 2; EZH2: Enhancer of Zeste Homolog 2; ASXL1: Additional Sex Combs Like 1; DNMT3A: DNA (cytosine-5-)-methyltransferase 3 Alpha; IDH1/2: Isocitrate Dehydrogenase 1/2; RPS14: Ribosomal Protein S14; CLL: Chronic Lymphocytic Leukemia


Tumor Protein 53 (p53) expressed from a gene TP53, located on the short arm of chromosome 17, is one of the seminal tumor suppressors. While germ line mutations of p53 result in a cancer predisposition syndrome, known as Li-Fraumeni Syndrome, somatic mutations have been described in as many as 50% of all cancers underscoring its role in tumor development [1-3]. Cellular functions of p53 under normal conditions are not clear as there are very low levels of p53 under normal conditions, but p53 levels increase under stress suggesting that it protects the cells from stress. Given the central role played by p53 in protecting the cells from stress and tumor development, the majority of clinical studies have explored the diagnostic and prognostic benefits of p53. In this review, we will discuss the regulation of p53, its activation under various stress conditions and inactivation due to mutations or aberrant expression, and implications of p53 mutations in pre-malignant cancer known as myelodysplastic syndromes (MDS).

The p53 auto-regulatory loop

As noted earlier, p53 levels are minimal under normal conditions and increase upon stress. The steady state levels of p53 under normal conditions are largely dependent on the protein Mouse Double Minute 2 homolog (MDM2) through an auto-regulatory feedback loop (Figure 1). P53 is able to induce transcription of MDM2 by binding to specific DNA elements on the MDM2 promoter region and the MDM2 protein then binds and effectively inactivates p53 [4]. MDM2 reduces p53 levels by its ability to act as an E3 ubiquitin ligase to ubiquitinate p53 and signaling it to the proteasome for degradation (Figure 1).