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The rate of spontaneous mutations in human myeloid cells

David J Araten1, Ondrej Krejci, Kimberly Ditata

  • 1Division of Hematology, Department of Veterans Affairs New York Harbor Healthcare System, United States; Division of Hematology, Department of Medicine, NYU School of Medicine and the NYU Langone Cancer Center, United States.

Mutation Research
|June 11, 2013
PubMed

Insights

Measuring the mutation rate (μ) in human myeloid cells is crucial for understanding leukemia. This study provides the first in vitro measurement of μ using the PIG-A gene, revealing insights into leukemogenesis.

Area of Science:

  • Hematology
  • Molecular Biology
  • Genetics

Background:

  • The mutation rate (μ) is a critical factor in leukemogenesis, but its measurement in human cells has been challenging.
  • The PIG-A gene offers advantages for mutation detection due to its X-linked nature and a readily detectable null phenotype via flow cytometry.

Purpose of the Study:

  • To provide the first in vitro measurement of the mutation rate (μ) in human myeloid cells.
  • To investigate the role of specific fusion genes (AML-ETO, MLL-AF9) and genetic alterations in myeloid cell hypermutability during leukemogenesis.

Main Methods:

  • Utilized CD34+ myeloid progenitor cells transduced with AML-ETO or MLL-AF9 fusion genes.
  • Employed the PIG-A gene assay for in vitro detection of spontaneous mutations and measured mutation rates per cell division.
  • Assessed the impact of p53 knockdown and mutations in NRAS or FLT3 on the mutation rate.

Main Results:

  • The median mutation rate (μ) in AML-ETO-transduced cells was approximately 9.4×10⁻⁷ per cell division.
  • MLL-AF9-transduced cells exhibited significantly fewer spontaneous mutations compared to AML-ETO cells.
  • Modifications in p53, NRAS, or FLT3 showed minimal effect on the measured mutation rates.

Conclusions:

  • This study establishes a method for measuring mutation rates in human myeloid cells, providing critical data for leukemogenesis research.
  • The findings suggest that the AML-ETO fusion gene is associated with a higher mutation rate in myeloid cells, potentially contributing to leukemogenesis.
  • A model is proposed to predict the necessity of hypermutability in the leukemogenesis process based on these experimental data.
Keywords:
AMLB-lymphoblastoid cell linesBLCLsGPIGPI-linked proteinsHuman myeloid culturesMutation rateMyeloid leukemia.PIG-A genePNHSpontaneous somatic mutationsacute myelogenous leukemiaglycosylphosphatidylinositolparoxysmal nocturnal hemoglobinuria

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