Abstract
Introduction FLT3 internal tandem duplication (ITD) mutations are found in around 25% of all acute myeloid leukaemia (AML) cases and is associated with shorter disease‐free and overall survival. Previous reports have shown that FLT3‐ITD induces a specific phenotype in leukemic blasts, which is characterized by high levels of CD33 and CD123, and that expression of CD33 and CD123 is directly influenced by the DNA FLT3‐ITD/wild‐type FLT3 allelic ratio (AR).MethodsA total of 42 FLT3‐ITD and 104 FLT3‐ITD–negative AML patients were analysed. Immunophenotyping data were used to calculate antigen expression levels as the ratio between the geometric mean fluorescence intensities (MFIs) of leukemic blasts and MFIs of negative lymphocyte populations. FLT3‐ITD‐DNA and RNA analysis was performed, under the same conditions, by capillary electrophoresis.ResultsCompared with the control group, the FLT3‐ITD cohort presented significantly higher CD7, CD33 and CD123 levels. In order to assess the impact of FLT3‐ITD abundance on antigen expression, the patients were grouped for each parameter into two cohorts using the following threshold values: (a) 0.5 for the AR, according to current AML guidelines; (b) 0.7 for the FLT3‐ITD/FLT3‐WT mRNA ratio (RR); and (c) 1.3 for the FLT3‐ITD RR/AR ratio. We found higher values of CD33 for RR/AR ≥1.3, and no other statistical differences between CD7, CD33 and CD123 levels of the other FLT3‐ITD groups. In terms of correlations between MFI values and FLT3‐ITD parameters, we only observed a moderate interdependence between CD33 MFI and the RR/AR ratio, and a weak negative correlation between CD123 MFI and AR.Conclusion FLT3‐ITD mutations induce a specific antigen profile in AML blasts, and our data do not onfirm previous reports of FLT3‐ITD AR influencing both CD33 and CD123 expression.
Highlights
FLT3 internal tandem duplication (ITD) mutations are found in around 25% of all acute myeloid leukaemia (AML) cases and is associated with shorter disease-free and overall survival
To further investigate the relation between CD33 mean fluorescence intensities (MFIs) values and the FLT3-ITD RR/allelic ratio (AR) ratio, we evaluated the repartition of NPM1 mutations within the two RR/AR groups, given that CD33 values are elevated in NPM1-mutated AMLs.[4,6,11]
The presence of FLT3-ITD correlated with a specific antigen profile, characterized by higher expression of CD7, CD33 and CD123 when compared to the FLT3-ITD–negative control population
Summary
Acute myeloid leukaemia (AML) with internal tandem duplication (ITD) insertions within the FLT3 gene represents around 25% of all AML cases, FLT3-ITD AML is not a distinct entity according to the 2016 revision of the World Health Organization classification.[3]. FLT3-ITD AML patients present high white blood cell counts, with a high percentage of bone marrow and circulating blasts. FLT3-ITD AML cells have a characteristic high CD33 and CD123 expression,[4,5,6] which was shown to be directly proportional to the DNA FLT3-ITD/FLT3-WT allelic ratio (AR).[4]. We investigated the quantitative expression of cell surface markers in FLT3-ITD AML from our local patient population, and evaluated the impact of both DNA and mRNA FLT3ITD/FLT3-WT ratios on antigen expression levels. Details regarding the assay and FLT3-ITD parameters are presented in Appendix S1—methods, results and Figure S2. FlT3-ITD–positive cases presented a significantly higher CD7, CD33 and CD123 expression when compared to the FLT3-ITD–negative control group (Figure 1) (Mann-Whitney U test; see Table S2)
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