Expression of myeloperoxidase and gene mutations in AML patients with normal karyotype: double CEBPA mutations are associated with high percentage of MPO positivity in leukemic blasts

Abstract

The percentage of myeloperoxidase (MPO)-positive blast cells is a simple and highly significant prognostic factor in AML patients. It has been reported that the high MPO group (MPO-H), in which >50% of blasts are MPO activity positive, is associated with favorable karyotypes, while the low MPO group (≤50% of blasts are MPO activity positive, MPO-L) is associated with adverse karyotypes. The MPO-H group shows better survival even when restricted to patients belonging to the intermediate chromosomal risk group or those with a normal karyotype. It has recently been shown that genotypes defined by the mutational status of NPM1, FLT3, and CEBPA are associated with treatment outcome in patients with cytogenetically normal AML. In this study, we aimed to evaluate the relationship between MPO positivity and gene mutations found in normal karyotypes. Sixty AML patients with normal karyotypes were included in this study. Blast cell MPO positivity was assessed in bone marrow smears stained for MPO. Associated genetic lesions (the NPM1, FLT3-ITD, and CEBPA mutations) were studied using nucleotide sequencing. Thirty-two patients were in the MPO-L group, and 28 patients in the MPO-H group. FLT3-ITD was found in 11 patients (18.3%), NPM1 mutations were found in 19 patients (31.7%), and CEBPA mutations were found in 11 patients (18.3%). In patients with CEBPA mutations, the carrying two simultaneous mutations (CEBPA double-mut ) was associated with high MPO expression, while the mutant NPM1 without FLT3-ITD genotype was not associated with MPO activity. Both higher MPO expression and the CEBPA double-mut genotype appeared to be associated with improved overall survival after intensive chemotherapy. Further studies are required to determine the importance of blast MPO activity as a prognostic factor, especially in CEBPA wild-type patients with a normal karyotype.

Distinct gene alterations with a high percentage of myeloperoxidase-positive leukemic blasts in de novo acute myeloid leukemia

“…CEBPA D-Mt was identified in the MPO-high group with high specificity, which was mutually exclusive with CBF-AML. Our previous analysis also indicated that CEBPA D-Mt was associated with high MPO-positivity in AML patients having normal karyotypes [14]. Therefore, the present study using a comprehensive analysis further confirmed the relationship between CEBPA D-Mt and MPO-positivity.…”

“…We previously revealed that the CEBPA double mutation (CEBPA D-Mt) was identified only among AML patients with a high percentage of MPO-positive blasts [14], and we also demonstrated that the MPO-positivity of AML blasts correlated with distinct DNA methylation profiling [15]. These findings suggest the presence of a specific relationship between MPO-positivity and gene mutations in AML.…”

Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and -M2 through boutique microarrays, real-time PCR and droplet digital PCR

“…Among the genes overexpressed in AML in the presented AML-array-based study, there were already-established AML markers, e.g., KIT , MYH11 , MN1 , MPO , SET and HOXA10 ( 44 , 47 , 48 ), genes associated with AML or potential biomarkers, such as STMN1 , CDK6 and ANGPT1 , or genes not yet discussed in the context of AML, such as RPLP0 or ENO1 , reported in neoplasms other than leukemia ( 49 , 50 ). As these genes often play fundamental roles in cell metabolism and function, their upregulation may be explained by the needs of the highly proliferating cancer cells.…”

Expression of myeloperoxidase in acute myeloid leukemia blasts mirrors the distinct DNA methylation pattern involving the downregulation of DNA methyltransferase DNMT3B

“…11,13,14 However, the leukemia blasts of t(8;21) AML, which has a RUNX1-RNXT1 fusion protein, were shown to be strongly positive for MPO, 15,16 though RUNX1-RUNXT1 acts in a dominant-negative manner for RUNX1. 17 Similarly, the very strong association between high MPO positivity of blasts and the presence of CEBPA double mutation was demonstrated in AML patients, 18 despite the dominant-negative function of CEBPA double mutation for wild-type CEBPA. 19 The dominant-negative manner in RUNX1-RUNXT1 and CEBPA double mutation may not be involved in the regulation of MPO transcription in AML blasts.…”