Utility of the p53 mutant protein in patients with low-risk myelodysplastic syndrome

In this issue of the Revista Brasileira de Hematologia e Hemoterapia, Duarte et al.¹ present data on the role of p53 protein expression and prognosis of patients with low-risk myelodysplastic syndrome (MDS). In a cohort of 38 patients, the authors demonstrated an association between mutant p53 protein expression and shortened survival.

MDS is a clinically heterogeneous disorder.² Patients with this condition demonstrate clonal hematopoietic expansion, cytopenias, myelodysplasia, ineffective hematopoiesis and an increased propensity to develop acute myeloid leukemia. Not surprisingly, prognosis is related to severity of cytopenias, presence of cytogenetic abnormalities and clonal evolution demonstrated by blast counts, and other 'traditional' prognostic elements. There is heterogeneity even among patients diagnosed with lower-risk disease, since a subset of these patients have more aggressive disease. Recent efforts have demonstrated that several molecular parameters linked to the pathophysiology of MDS may affect overall survival.^{3 , 4} Thus, identification of additional prognosticators that more accurately characterize subgroups and their outcomes are essential.

Current understanding of the pathophysiology of MDS indicates that there are founding mutations in a hematopoietic stem cell that ultimately offer a survival advantage to the affected cell(s). These mutations occur in genes encoding protein products that are involved typically in either RNA splicing or DNA methylation, which in turn leads to genomic instability and further mutations.⁵ The survival advantage in mutated cells usually leads to a dominant bone marrow progenitor clone. This clone can subsequently acquire additional driver mutations that lead to the development of multiple subclonal populations. The accumulation and combination of these genetic lesions likely contribute to the phenotypes observed in MDS patients. TP53 gene mutations are particularly interesting given the fact that its protein product has tumor suppression activity.

TP53 encodes a cytoplasmic protein p53 that regulates cell growth and death. Mutations have been identified in a variety of cancers.⁶ In MDS, TP53 mutations have been found mainly in intermediate- to high-risk patients. Patients often present with complex cytogenetic abnormalities, severe thrombocytopenia, increased risk of leukemia progression, and have shorter survival.^{7 , 8} While it has been well documented that genetic lesions in TP53carry an independent poor prognostic value, mostly amongst advanced stage patients,^{9 , 10} the role of TP53 mutations in low-risk MDS remains unclear. Duarte et al. examined whether intracellular accumulation of mutant p53 correlates with clinical characteristics and prognosis among 38 patients with low-risk MDS (defined by current scoring system).¹ Patients with mutant p53 were older, anemic and leukopenic at the time of diagnosis, and had a shorter median survival compared to those carrying wild-type p53.

Duarte et al. concluded that molecular identification of mutant p53 contributes to risk stratification of patients with low-risk MDS, which may alter the treatment approach.¹ The authors provide a compelling argument for further characterization of the role of p53 in a larger cohort of low-risk MDS patients.

Interpreting p53 mutation role in MDS is not a trivial task, however, since there are often complicating interactions with other intracellular regulators.¹¹ A recent effort to characterize genetic lesions in MDS showed that each patient frequently harbors mutations in multiple genes simultaneously.⁸ In another study, mutations in genes ASXL1, EZH2, RUNX1, NRAS and others were associated with shorter overall survival in lower-risk MDS.¹² Interestingly, interactions among these gene products and p53 have been documented extensively.^{13 , 14}

Over the past 5-10 years a variety of technologies have improved and enabled high-throughput analysis of entire MDS genomes, leading to the identification of several new potentially targetable genes implicated in MDS pathogenesis. The challenge is how to incorporate these into new prognostic systems. In addition, it is expected that these approaches will lead to therapeutic insights that are desperately needed for MDS patients.

REFERENCES

• ¹
  Duarte FB, Gonçalves RP, Barbosa MC, Rocha Filho FD, Santos TE, Santos TN, et al. Tumor suppressor p53 protein expression: prognostic significance in patients with low-risk myelodysplastic syndrome. Rev Bras Hematol Hemoter. 2014;36:196-201.
• ²
  Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K, et al. Clonal architecture of secondary acute myeloid leukemia. N Engl J Med. 2012;366:1090-8.
• ³
  Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, et al. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998;12:887-92.
• ⁴
  Paquette RL, Landaw EM, Pierre RV, Kahan J, Lübbert M, Lazcano O, et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood. 1993;82:590-9.
• ⁵
  Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood. 2013;122:4021-34.
• ⁶
  Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546-58.
• ⁷
  Kulasekararaj AG, Smith AE, Mian SA, Mohamedali AM, Krishnamurthy P, Lea NC, et al. TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Br J Haematol. 2013;160:660-72.
• ⁸
  Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496-506.
• ⁹
  Horiike S, Kita-Sasai Y, Nakao M, Taniwaki M. Configuration of the TP53 gene as an independent prognostic parameter of myelodysplastic syndrome. Leuk Lymphoma. 2003;44:915-22.
• ¹⁰
  Kita-Sasai Y, Horiike S, Misawa S, Kaneko H, Kobayashi M, Nakao M, et al. International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome. Br J Haematol. 2001;115:309-12.
• ¹¹
  Vogelstein B, Lane D, Levine A. Surfing the p53 network. Nature. 2000;408:307-10.
• ¹²
  Bejar R, Stevenson KE, Caughey BA, Abdel-Wahab O, Steensma DP, Galili N, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2012;30:3376-82.
• ¹³
  Yang Y, Wang C, Zhang P, Gao K, Wang D, Yu H, et al. Polycomb group protein PHF1 regulates p53-dependent cell growth arrest and apoptosis. J Biol Chem. 2013;288:529-39.
• ¹⁴
  Kaindl U, Morak M, Portsmouth C, Mecklenbräuker A, Kauer M, Zeginigg M, et al. Blocking ETV6/RUNX1-induced MDM2 overexpression by Nutlin-3 reactivates p53 signaling in childhood leukemia. Leukemia. 2013.

Publication Dates

• Publication in this collection
  May-Jun 2014