Evidence that a mutation in the MLH1 3′-untranslated region confers a mutator phenotype and mismatch repair deficiency in patients with relapsed leukemia

Guogen Mao, Xiaoyu Pan, Liya Gu

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Defects in DNA mismatch repair (MMR) are the molecular basis of certain cancers, including hematological malignancies. The defects are often caused by mutations in coding regions of MMR genes or promoter methylation of the genes. However, in many cases, despite that a hypermutable phenotype is detected in a patient, no mutations/hypermethylations of MMR genes can be detected. We report here a novel mechanism that a mutation in the MLH1 3′-untranslated region (3′-UTR) leads to MMR deficiency. A relapsed leukemia patient displayed microsatellite instability, but no genetic and epigenetic alterations in key MMR genes were identifiable. Instead, a 3-nucleotide (TTC) deletion in the MLH1 3′-UTR was found in the patient's blood sample. The mutant MLH1 3′-UTR was found to significantly reduce the expressions of both a firefly luciferase reporter gene and an ectopic MLH1 gene in model cell lines. Consistent with these observations, a significant reduction in the steady-state level of MLH1 mRNA was observed in white blood cells of the patient. These findings suggest that the mutant MLH1 3′-UTR can cause a severely reduced/defective MMR activity conferring leukemia relapse, likely by down-regulating MLH1 expression at the mRNA level. Although the exact mechanism by which the mutant 3′-UTR down-regulates the MLH1 mRNA is not known, our findings provide a novel marker for cancers with MMR defects.

Original languageEnglish (US)
Pages (from-to)3211-3216
Number of pages6
JournalJournal of Biological Chemistry
Volume283
Issue number6
DOIs
StatePublished - Feb 8 2008

Fingerprint

DNA Mismatch Repair
3' Untranslated Regions
Leukemia
Repair
Phenotype
Genes
Mutation
Messenger RNA
Defects
Blood
Firefly Luciferases
Cells
Microsatellite Instability
Hematologic Neoplasms
Methylation
Reporter Genes
Epigenomics
Turcot syndrome
Neoplasms
Microsatellite Repeats

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

@article{b23125ded6ad4e318220a75775ae3875,
title = "Evidence that a mutation in the MLH1 3′-untranslated region confers a mutator phenotype and mismatch repair deficiency in patients with relapsed leukemia",
abstract = "Defects in DNA mismatch repair (MMR) are the molecular basis of certain cancers, including hematological malignancies. The defects are often caused by mutations in coding regions of MMR genes or promoter methylation of the genes. However, in many cases, despite that a hypermutable phenotype is detected in a patient, no mutations/hypermethylations of MMR genes can be detected. We report here a novel mechanism that a mutation in the MLH1 3′-untranslated region (3′-UTR) leads to MMR deficiency. A relapsed leukemia patient displayed microsatellite instability, but no genetic and epigenetic alterations in key MMR genes were identifiable. Instead, a 3-nucleotide (TTC) deletion in the MLH1 3′-UTR was found in the patient's blood sample. The mutant MLH1 3′-UTR was found to significantly reduce the expressions of both a firefly luciferase reporter gene and an ectopic MLH1 gene in model cell lines. Consistent with these observations, a significant reduction in the steady-state level of MLH1 mRNA was observed in white blood cells of the patient. These findings suggest that the mutant MLH1 3′-UTR can cause a severely reduced/defective MMR activity conferring leukemia relapse, likely by down-regulating MLH1 expression at the mRNA level. Although the exact mechanism by which the mutant 3′-UTR down-regulates the MLH1 mRNA is not known, our findings provide a novel marker for cancers with MMR defects.",
author = "Guogen Mao and Xiaoyu Pan and Liya Gu",
year = "2008",
month = "2",
day = "8",
doi = "10.1074/jbc.M709276200",
language = "English (US)",
volume = "283",
pages = "3211--3216",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Evidence that a mutation in the MLH1 3′-untranslated region confers a mutator phenotype and mismatch repair deficiency in patients with relapsed leukemia

AU - Mao, Guogen

AU - Pan, Xiaoyu

AU - Gu, Liya

PY - 2008/2/8

Y1 - 2008/2/8

N2 - Defects in DNA mismatch repair (MMR) are the molecular basis of certain cancers, including hematological malignancies. The defects are often caused by mutations in coding regions of MMR genes or promoter methylation of the genes. However, in many cases, despite that a hypermutable phenotype is detected in a patient, no mutations/hypermethylations of MMR genes can be detected. We report here a novel mechanism that a mutation in the MLH1 3′-untranslated region (3′-UTR) leads to MMR deficiency. A relapsed leukemia patient displayed microsatellite instability, but no genetic and epigenetic alterations in key MMR genes were identifiable. Instead, a 3-nucleotide (TTC) deletion in the MLH1 3′-UTR was found in the patient's blood sample. The mutant MLH1 3′-UTR was found to significantly reduce the expressions of both a firefly luciferase reporter gene and an ectopic MLH1 gene in model cell lines. Consistent with these observations, a significant reduction in the steady-state level of MLH1 mRNA was observed in white blood cells of the patient. These findings suggest that the mutant MLH1 3′-UTR can cause a severely reduced/defective MMR activity conferring leukemia relapse, likely by down-regulating MLH1 expression at the mRNA level. Although the exact mechanism by which the mutant 3′-UTR down-regulates the MLH1 mRNA is not known, our findings provide a novel marker for cancers with MMR defects.

AB - Defects in DNA mismatch repair (MMR) are the molecular basis of certain cancers, including hematological malignancies. The defects are often caused by mutations in coding regions of MMR genes or promoter methylation of the genes. However, in many cases, despite that a hypermutable phenotype is detected in a patient, no mutations/hypermethylations of MMR genes can be detected. We report here a novel mechanism that a mutation in the MLH1 3′-untranslated region (3′-UTR) leads to MMR deficiency. A relapsed leukemia patient displayed microsatellite instability, but no genetic and epigenetic alterations in key MMR genes were identifiable. Instead, a 3-nucleotide (TTC) deletion in the MLH1 3′-UTR was found in the patient's blood sample. The mutant MLH1 3′-UTR was found to significantly reduce the expressions of both a firefly luciferase reporter gene and an ectopic MLH1 gene in model cell lines. Consistent with these observations, a significant reduction in the steady-state level of MLH1 mRNA was observed in white blood cells of the patient. These findings suggest that the mutant MLH1 3′-UTR can cause a severely reduced/defective MMR activity conferring leukemia relapse, likely by down-regulating MLH1 expression at the mRNA level. Although the exact mechanism by which the mutant 3′-UTR down-regulates the MLH1 mRNA is not known, our findings provide a novel marker for cancers with MMR defects.

UR - http://www.scopus.com/inward/record.url?scp=41249086157&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41249086157&partnerID=8YFLogxK

U2 - 10.1074/jbc.M709276200

DO - 10.1074/jbc.M709276200

M3 - Article

C2 - 18056700

AN - SCOPUS:41249086157

VL - 283

SP - 3211

EP - 3216

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -