DNMT3A,   IDH1/2,  TET2,  General AML

Gene alterations associated with myeloperoxidase positivity in de novo AML – a Japanese study

Myeloperoxidase (MPO), is a microbicidal protein, whose expression is a definite marker for diagnosis of Acute Myeloid Leukemia (AML) and findings from clinical studies conducted by the Japan Adult Leukemia Study Group (JALSG) have shown that MPO is a significant prognostic factor in AML. Rena Kamijo from Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan, and colleagues, investigated the relationship between MPO positivity and gene alterations. The data from the study were reported in Leukemia Research earlier this month.

In this study, Kamijo et al. performed targeted sequencing for 51 genes and 10 chimeric genes on bone marrow samples from 164 adults with newly diagnosed de novo AML who were treated in the JALSG AML201 study. Patients were divided into two groups based on the positivity of the MPO enzymatic activity including > 50% MPO-positive blasts (MPO high group, n = 107 [median age = 46 years]) and ≤ 50% MPO-positive blasts (MPO low group, n = 57 [median age = 51 years])

Key findings:
  • Mutations in 44 genes and 6 fusion transcripts were identified in all patients
  • Mean number of mutated genes in the MPO-high and MPO-low groups were 2.61 ±72 and 2.37 ± 0.19, respectively
  • Mutations in CBF-fusion gene, (P < 0.001), KIT gene (P < 0.001), CEBPA double mutation (P < 0.001) correlated with MPO high group
  • Low MPO positivity correlated with mutations in DNTM3A (P = 0.001), TP53 (P = 0.02) and FLT3-TKD (P = 0.004)
  • Analysis in non-CBF AML patients
    • Mutations in IDH1/2, TET2 and WT1 correlated with high MPO positivity; P = 0.001

In summary, this is the first study to assess MPO-positivity as a marker for distinct gene alterations. It was demonstrated in this study that MPO-positivity of blasts correlates with distinct gene alterations among de novo AML patients. Additionally, high MPO positivity was shown to correlate with distinct DNA methylation profile.

Kamijo et al. noted that their study is limited by the fact that the impact of some mutated genes could not be identified due to low frequencies. Moreover, the position and type of each gene affected by MPO positivity was insufficient.

References
  1. Kamijo R. et al. Distinct gene alterations with a high percentage of myeloperoxidase-positive leukemic blasts in de novo acute myeloid leukemia. Leuk Res. 2018 Jan 2. DOI: 10.1016/j.leukres.2017.12.006. [Epub ahead of print].

Expert Opinion

 AML genotype-phenotype relationship form a view of myeloperoxidase-positivity

Acute myeloid leukemia (AML) is a group of biologically heterogeneous diseases as reflected by variety in morphology of leukemic cells. The myeloperoxidase positivity of leukemia blasts using cytochemistry was regarded as not only a golden marker of the diagnosis of AML, but also a prognostic indicator for outcomes after intensive chemotherapy. Recent years, next-generation sequencing have shown that acquired genetic alterations have an essential role in the molecular pathogenesis of AML. However, the relationship between genetic alterations and morphology of leukemia blasts are yet poorly understood. In the report by Kamijo and colleagues, they advanced the knowledge of the genotype-phenotype associations in AML. They conducted a comprehensive genetic analysis of 164 patients, and investigated their relationship with morphological findings, using data registered in the Japan Adult Leukemia Study Group AML 201 study. It was suggested that the myeloperoxidase positivity of leukemia blasts directly reflected the underlying gene mutational status. The present study indicated that morphology of leukemia cells had significant relationship with genetic alterations in AML, and the further attempts are necessary to integrate cytogenetics, molecular genetics, and morphological data to generate better prognostic system for AML. Large clinical study is warranted for this purpose.  

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