FLT3 expression and IL10 promoter polymorphism in acute myeloid leukemia with RUNX1-RUNX1T1

Abstract

We investigated the correlation between FLT3 expression and IL10 gene promoter polymorphism in acute myeloid leukemia with RUNX1-RUNX1T1 and their clinical significance. FLT3 mRNA expression was measured by real-time quantitative PCR (qPCR) and immunohistochemical staining (IHC) on bone marrow (BM) leukemic cells. IL10 gene promoter polymorphisms including rs1800896 (G-1082A), rs1800871 (C-819T), and rs1800872 (C-592T) were genotyped by direct sequencing. Among 45 enrolled patients, 32 (71.1 %) exhibited FLT3 overexpression, whose FLT3 mRNA level was higher than normal cut-off value (0.02). The IHC results also consisted with FLT3 mRNA expression data achieved by qPCR. The FLT3 mRNA level was significantly different among 3 IHC staining groups (P < 0.0001); 0.031 ± 0.041, 0.106 ± 0.097 and 0.588 ± 0.573 in IHC negative, intermediate and positive group, respectively. Interestingly, the FLT3 expression level was correlated with the percentage of BM CD34 positive cells (R = 0.360, P = 0.016). The elevated FLT3 expression at initial BM were decreased after remission and maintained lower than the cut-off level. FLT3 expression was not dependent on IL10 gene promoter polymorphisms. FLT3 overexpression itself did not demonstrate significant effects on overall survival (OS). However, it is notable that IL10 rs1800896 GA genotype tended to have a lower estimated mean OS (20.1 months) compared to GG genotype (54.6 months), but the statistical significance was not derived because of limited number of patients in this study (P = 0.072). Further studies including more type of leukemia and patients may be helpful to understand the relations between cytokine genotype and FLT3 expression and their prognostic impact.

Cytokine rs361525, rs1800750, rs1800629, rs1800896, rs1800872, rs1800795, rs1800470, and rs2430561 SNPs in relation with prognostic factors in acute myeloid leukemia

“…In contradiction, Kim et al reported a lower OS (estimated 20.1 months) in case of the GA variant genotype compared to GG homozygous genotype (estimated 54.6 months) for the IL-10 rs1800896 SNP in AML patients. 36 Similar to our findings, Kim et al, revealed that the IL-10 rs1800871 and rs1800872 variant genotypes did not have an effect on OS. 36 Similar results regarding this lack of effect on OS by IL-10 rs1800871 have been previously reported.…”

“…36 Similar to our findings, Kim et al, revealed that the IL-10 rs1800871 and rs1800872 variant genotypes did not have an effect on OS. 36 Similar results regarding this lack of effect on OS by IL-10 rs1800871 have been previously reported. 37 Pehlivan et al found no association between TNF-α rs1800629, IL-10 rs1800872, rs1800871, and rs1800896, IFN-γ rs2430561, and TGF-β1 rs1800470 (codons 10 and 25) polymorphisms and OS in their Turkish CML patients, 13 being therefore in line with our observations.…”

“…We observed a trend towards statistical significance regarding the association between the TNF‐α rs1800629 variant genotype and OS. In contradiction, Kim et al reported a lower OS (estimated 20.1 months) in case of the GA variant genotype compared to GG homozygous genotype (estimated 54.6 months) for the IL‐10 rs1800896 SNP in AML patients . Similar to our findings, Kim et al, revealed that the IL‐10 rs1800871 and rs1800872 variant genotypes did not have an effect on OS .…”

Gene mutation profile and risk stratification in AML1‑ETO‑positive acute myeloid leukemia based on next‑generation sequencing

“…The c-KIT mutation has been proven to cooperate with the AML1-ETO fusion to induce leukemia (3,5). Still there are other gene mutations, including WT1, FLT3-ITD and PDGFR mutations, that have been reported to be involved in the progression of this subtype of leukemia (6–8), further supporting an oncogenic cooperation in leukemogenesis between RUNX1-RUNX1T1 and additional molecular alterations. Therefore, detailed detection of the gene mutation profile at diagnosis and relapse could deepen the understanding of leukemia development and progression.…”

Cytogenetic characteristics of and prognosis for acute myeloid leukemia in 107 children

“…This might be related to the formation of RUNX1-RUNX1T1 producing multiple proteins in the nucleus and cytoplasm [ 28 , 29 ]. Some mutations, such as FLT3 mutations [ 30 ] and miRNA overexpression [ 31 ], also affect the prognoses of RUNX1-RUNX1T1 positive patients. There are about 25% of patients with t(8;21) or positive RUNX1-RUNX1T1 fusion gene that also has c- KIT mutations, changing the prognosis from good to moderate [ 32 ].…”