Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia

Potential contribution to AML progression

Guogen Mao, Fenghua Yuan, Kimberly Absher, C. Darrell Jennings, Dianna S. Howard, Craig T. Jordan, Liya Gu

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)281-289
Number of pages9
JournalCell Research
Volume18
Issue number2
DOIs
StatePublished - Feb 1 2008

Fingerprint

DNA Mismatch Repair
Acute Myeloid Leukemia
Mutation
Recurrence
Genes
Leukemia
Amino Acids

Keywords

  • Hypermethylation
  • Leukemia relapse
  • MLH1
  • MSH2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia : Potential contribution to AML progression. / Mao, Guogen; Yuan, Fenghua; Absher, Kimberly; Jennings, C. Darrell; Howard, Dianna S.; Jordan, Craig T.; Gu, Liya.

In: Cell Research, Vol. 18, No. 2, 01.02.2008, p. 281-289.

Research output: Contribution to journalArticle

Mao, Guogen ; Yuan, Fenghua ; Absher, Kimberly ; Jennings, C. Darrell ; Howard, Dianna S. ; Jordan, Craig T. ; Gu, Liya. / Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia : Potential contribution to AML progression. In: Cell Research. 2008 ; Vol. 18, No. 2. pp. 281-289.
@article{a753e6ac8272491b9aebb45eb55c2a65,
title = "Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia: Potential contribution to AML progression",
abstract = "Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.",
keywords = "Hypermethylation, Leukemia relapse, MLH1, MSH2",
author = "Guogen Mao and Fenghua Yuan and Kimberly Absher and Jennings, {C. Darrell} and Howard, {Dianna S.} and Jordan, {Craig T.} and Liya Gu",
year = "2008",
month = "2",
day = "1",
doi = "10.1038/cr.2008.14",
language = "English (US)",
volume = "18",
pages = "281--289",
journal = "Cell Research",
issn = "1001-0602",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Preferential loss of mismatch repair function in refractory and relapsed acute myeloid leukemia

T2 - Potential contribution to AML progression

AU - Mao, Guogen

AU - Yuan, Fenghua

AU - Absher, Kimberly

AU - Jennings, C. Darrell

AU - Howard, Dianna S.

AU - Jordan, Craig T.

AU - Gu, Liya

PY - 2008/2/1

Y1 - 2008/2/1

N2 - Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.

AB - Acute myeloid leukemia (AML) is an aggressive hematological cancer. Despite therapeutic regimens that lead to complete remission, the vast majority of patients undergo relapse. The molecular mechanisms underlying AML development and relapse remain incompletely defined. To explore whether loss of DNA mismatch repair (MMR) function is involved in AML, we screened two key MMR genes, MSH2 and MLH1, for mutations and promoter hypermethylation in leukemia specimens from 53 AML patients and blood from 17 non-cancer controls. We show here that whereas no amino acid alteration or promoter hypermethylation was detected in all control samples, 18 AML patients exhibited either mutations in MMR genes or hypermethylation in the MLH1 promoter. In vitro functional MMR analysis revealed that almost all the mutations analyzed resulted in loss of MMR function. MMR defects were significantly more frequent in patients with refractory or relapsed AML compared with newly diagnosed patients. These observations suggest for the first time that the loss of MMR function is associated with refractory and relapsed AML and may contribute to disease pathogenesis.

KW - Hypermethylation

KW - Leukemia relapse

KW - MLH1

KW - MSH2

UR - http://www.scopus.com/inward/record.url?scp=38849153665&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38849153665&partnerID=8YFLogxK

U2 - 10.1038/cr.2008.14

DO - 10.1038/cr.2008.14

M3 - Article

VL - 18

SP - 281

EP - 289

JO - Cell Research

JF - Cell Research

SN - 1001-0602

IS - 2

ER -