The Influence of FLT3-ITD Mutation on Baseline Levels of Selected Cytokines and Soluble Adhesion Molecules in Acute Myeloid Leukemia with Mutated NPM-1

Introduction: Cytokines and adhesion molecules have been studied as markers of immune system activation in various diseases including AML/MDS. These factors form a dynamic network which affects AML cell susceptibility to chemotherapy. We analyzed whether these factors may be associated with mutations specific for AML. The aim of our study was to evaluate hypothesis that baseline serum levels of these factors may be associated with mutation profile on the model of AML with mutation in NPM-1 and FLT3-ITD.

Methods: A total of 42 de novo AML patients (age 55.9 ± 11.5, median 60 years; 16 males, 26 females; all Caucasian) were analyzed. All patients had normal karyotype and mutation in NPM-1, 25 patients had mutation in FLT3-ITD. The subgroups have not differed in age. We evaluated baseline circulating levels of the following factors: interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10), epidermal growth factor (EGF), interferon-gamma (IFN-γ), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), E-selectin (E-SEL), P-selectin (P-SEL), L-selectin (L-SEL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). All biomarkers were measured by biochip array technology on Evidence Investigator analyzer (Randox). Probability values (P) < 0.05 were considered statistically significant.

Results: The cases with FLT3-ITD mutation had higher levels of E-SEL (51.90 ± 19.90 mcg/L vs. 23.85 ± 14.07 mcg/L; p = 0.002), P-SEL (192.01 ± 77.29 mcg/L vs. 127.89 ± 48.47 mcg/L; p = 0.035) and lower levels of EGF (7.01 ± 7.08 ng/L vs. 20.64 ± 16.73 ng/L; p = 0.019) and TNF-α (3.55 ± 1.89 ng/L vs. 5.69 ± 3.55 ng/L; p = 0.049). The levels of L-SEL were higher in FLT3-ITD mutated AML, which was not statistically significant, possibly due to exceeding the upper limit or array sensitivity in majority of cases. The differences in baseline levels of other evaluated markers were not statistically significant.

Conclusions: Cytokines are an important part of cancer environment. In patients with normal karyotype and mutation in NPM-1, the presence of FLT3-ITD influenced levels of EGF, TNF-α, E-SEL, P-SEL and possibly L-SEL. Whether these findings are associated with adverse biology of FLT3-ITD positive leukemia is not known at the moment and requires further elucidation.