p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621).

[1]  G Mike Makrigiorgos,et al.  NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes , 2013, Leukemia.

[2]  G. Mufti,et al.  TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis , 2013, British journal of haematology.

[3]  M. Saha,et al.  p53 nuclear expression correlates with hemizygous TP53 deletion and predicts an adverse outcome for patients with relapsed/refractory multiple myeloma treated with lenalidomide. , 2012, American journal of clinical pathology.

[4]  R. Schlenk,et al.  Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study , 2012, Leukemia.

[5]  M. Cazzola,et al.  A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. , 2011, Blood.

[6]  D. Neuberg,et al.  Clinical effect of point mutations in myelodysplastic syndromes. , 2011, The New England journal of medicine.

[7]  Eva Hellström-Lindberg,et al.  TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  C. Steidl,et al.  Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q , 2011, Leukemia.

[9]  P. Fenaux,et al.  [The 5q- syndrome]. , 2010, La Revue du praticien.

[10]  S. Pileri,et al.  Induction of p53 and up-regulation of the p53 pathway in the human 5q- syndrome. , 2010, Blood.

[11]  A. Warren,et al.  A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q− syndrome , 2009, Nature Medicine.

[12]  M. McDevitt,et al.  TP53 Mutations in Myeloid Malignancies are either Homozygous or Hemizygous due to Copy Number-Neutral Loss of Heterozygosity or Deletion of 17p , 2009, Leukemia.

[13]  M. Dimopoulos,et al.  Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies , 2010, Leukemia.

[14]  Hong Chang,et al.  Aberrant nuclear p53 expression predicts hemizygous 17p (TP53) deletion in chronic lymphocytic leukemia. , 2010, American journal of clinical pathology.

[15]  E. Hellström-Lindberg,et al.  Patients with del(5q) MDS who fail to achieve sustained erythroid or cytogenetic remission after treatment with lenalidomide have an increased risk for clonal evolution and AML progression , 2010, Annals of Hematology.

[16]  L. Saft,et al.  Clonal heterogeneity in the 5q- syndrome: p53 expressing progenitors prevail during lenalidomide treatment and expand at disease progression , 2009, Haematologica.

[17]  J. Issa,et al.  The heterogeneous prognosis of patients with myelodysplastic syndrome and chromosome 5 abnormalities , 2009, Cancer.

[18]  L. Abruzzo,et al.  p53 expression by immunohistochemistry is an important determinant of survival in patients with chronic lymphocytic leukemia receiving frontline chemo-immunotherapy , 2009, Leukemia & lymphoma.

[19]  J. Maciejewski,et al.  Myelodysplastic syndromes with del(5q): indications and strategies for cytogenetic testing. , 2008, Cancer genetics and cytogenetics.

[20]  J. Issa,et al.  The Heterogeneous Prognosis of Patients with Myelodysplastic Syndrome (MDS) and Chromosome 5 Abnormalities: How Does It Relate to the Original Lenalidomide Experience in MDS?. , 2008 .

[21]  T. Murate,et al.  Characterization of myelodysplastic syndrome and aplastic anemia by immunostaining of p53 and hemoglobin F and karyotype analysis: Differential diagnosis between refractory anemia and aplastic anemia , 2008, Pathology international.

[22]  D. Christiansen,et al.  Genetics of therapy-related myelodysplasia and acute myeloid leukemia , 2008, Leukemia.

[23]  Hong Chang,et al.  Aberrant nuclear p53 protein expression detected by immunohistochemistry is associated with hemizygous P53 deletion and poor survival for multiple myeloma , 2007, British journal of haematology.

[24]  H. Kamata,et al.  Mutation of the p53 tumour suppressor gene and overexpression of its protein in 62 Japanese non-Hodgkin’s lymphomas , 2007, Clinical and Experimental Medicine.

[25]  U. Germing,et al.  Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. , 2006, Haematologica.

[26]  J. D. van der Walt,et al.  European consensus on grading bone marrow fibrosis and assessment of cellularity. , 2005, Haematologica.

[27]  U. Moll,et al.  The MDM2-p53 interaction. , 2003, Molecular cancer research : MCR.

[28]  M. Taniwaki,et al.  Configuration of the TP53 Gene as an Independent Prognostic Parameter of Myelodysplastic Syndrome , 2003, Leukemia & lymphoma.

[29]  喜多 ゆり,et al.  International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome , 2003 .

[30]  U. Moll,et al.  The MDM 2p 53 Interaction , 2003 .

[31]  B. Alter,et al.  p53 protein overexpression in bone marrow biopsies of patients with Shwachman-Diamond syndrome has a prevalence similar to that of patients with refractory anemia. , 2002, Archives of pathology & laboratory medicine.

[32]  I. Pollack,et al.  Expression of p53 and prognosis in children with malignant gliomas. , 2002, The New England journal of medicine.

[33]  Q. Xue,et al.  Aberrant expression of pRb, p16, p14ARF, MDM2, p21 and p53 in stage I adenocarcinomas of the lung , 2002, Pathology international.

[34]  J. Wainscoat,et al.  The 5 q-Syndrome , 2002 .

[35]  M. Taniwaki,et al.  International prognostic scoring system and TP53 mutations are independent prognostic indicators for patients with myelodysplastic syndrome , 2001, British journal of haematology.

[36]  K. Sugimachi,et al.  Heterogeneous distribution of P53 immunoreactivity in human lung adenocarcinoma correlates with MDM2 protein expression, rather than with P53 gene mutation , 2001, International journal of cancer.

[37]  D. Christiansen,et al.  Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  T. Naoe,et al.  Prognostic value of p53 gene mutations and the product expression in de novo acute myeloid leukemia , 2000, European journal of haematology.

[39]  N. Aoki,et al.  Study of p53 in elderly patients with myelodysplastic syndromes by immunohistochemistry and DNA analysis. , 1999, The American journal of pathology.

[40]  M. Taniwaki,et al.  Distinct genetic involvement of the TP53 gene in therapy-related leukemia and myelodysplasia with chromosomal losses of Nos 5 and/or 7 and its possible relationship to replication error phenotype , 1999, Leukemia.

[41]  S. Yagihashi,et al.  Apoptosis, bcl-2 Expression and p53 Accumulation in Myelodysplastic Syndrome, Myelodysplastic-Syndrome-Derived Acute Myelogenous Leukemia and de novo Acute Myelogenous Leukemia , 1999, Acta Haematologica.

[42]  菊川 昌幸.  Study of p53 in elderly patients with myelodysplastic syndromes by immunohistochemistry and DNA analysis , 1999 .

[43]  S. Chevret,et al.  RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up , 1998, Leukemia.

[44]  M. Tschan,et al.  Expression of p16INK4a/p16alpha and p19ARF/p16beta is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. , 1998, Oncogene.

[45]  T Hamblin,et al.  International scoring system for evaluating prognosis in myelodysplastic syndromes. , 1997, Blood.

[46]  D. Huhn,et al.  Analysis of the p53 and MDM‐2 gene in acute myeloid leukemia , 1996, European journal of haematology.

[47]  H. Kaneko,et al.  TP53 mutations emerge at early phase of myelodysplastic syndrome and are associated with complex chromosomal abnormalities. , 1995, Blood.

[48]  E. Wattel,et al.  Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoïesis and a high incidence of P53 mutations. , 1995, Leukemia.

[49]  D. J. King,et al.  p53 mutation in the myelodysplastic syndromes , 1995, British journal of haematology.

[50]  B. Quesnel,et al.  p53 Mutations Are Associated With Resistance to Chemotherapy and Short Survival in Hematologic Malignancies , 1994 .

[51]  M. Kitagawa,et al.  p53 expression in myeloid cells of myelodysplastic syndromes. Association with evolution of overt leukemia. , 1994, The American journal of pathology.

[52]  B. Quesnel,et al.  p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. , 1994, Blood.

[53]  Koichi Sugimoto,et al.  Mutations of the p53 gene in myelodysplastic syndrome (MDS) and MDS-derived leukemia. , 1993, Blood.

[54]  W. McGuire,et al.  Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. , 1993, Journal of the National Cancer Institute.

[55]  A. Schulz,et al.  P53 mutations in myelodysplastic syndromes. , 1992, Leukemia.

[56]  R. Berger,et al.  Mutations in the p53 gene in myelodysplastic syndromes. , 1991, Oncogene.