HDM4 (HDMX) Is Widely Expressed in Adult pre-B Acute Lymphoblastic Leukemia and Is a Potential Therapeutic Target

Mod Pathol. 2007 Jan;20(1):54-62. doi: 10.1038/modpathol.3800727. Epub 2006 Nov 24.

Abstract

Human homolog of murine double minute 2 (HDM2) and HDM4 (or HDMX) are negative regulators of p53. HDM4 has not been assessed in precursor B (pre-B) lymphoblastic leukemia (ALL). We examined bone marrow samples obtained at time of diagnosis from 55 adults with pre-B ALL. A tissue microarray composed of 2 cores per specimen was constructed and immunohistochemical techniques were used to assess HDM4, HDM2, p53, and p21. HDM4 was expressed in 39 of 49 (80%) cases. HDM2 was expressed in 14 of 54 (26%). All HDM2-positive cases were also positive for HDM4 (P<0.05). We confirmed expression of HDM4 and HDM4 variants by Western blotting and sequencing of reverse transcription-polymerase chain reaction products in a subset of ALL tumors. Results were correlated with the presence of the Philadelphia chromosome (Ph). p53 (P<0.05) and p21 (P<0.001) were expressed significantly more often in Ph+ pre-B ALL. HDM4 and HDM2 showed no correlation with Ph status. HDM4 expression in most cases of adult pre-B ALL suggests that HDM4 is a potential therapeutic target.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / analysis*
  • Biomarkers, Tumor / genetics
  • Bone Marrow / chemistry
  • Bone Marrow / pathology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / analysis
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Mutation
  • Nuclear Proteins / analysis*
  • Philadelphia Chromosome
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins / analysis*
  • Proto-Oncogene Proteins c-mdm2 / analysis
  • RNA, Messenger / analysis
  • Time Factors
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • MDM4 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2