The prognostic role of C-KIT, TET1 and TET2 gene expression in Acute Myeloid Leukemia

Abstract

Aim was to assess the role of C-KIT, TET1 and TET2 expression in the diagnosis and prognosis of acute myeloblastic leukemia (AML). Methods The expression levels of C-KIT, TET1 and TET2 were assessed in the bone marrow (BM) aspirate of 152 AML patients compared to 20 healthy control using quantitative real-time polymerase chain reaction (qRT-PCR). Data were correlated with the clinico-pathological features of the patients, response to treatment, disease-free survival (DFS), and overall survival (OS) rates. Results C-KIT, TET1 and TET2 were significantly upregulated in AML patients [0.25 (0–11.6), 0.0113 (0–3.301), and 0.07 (0–4); respectively], compared to the control group [0.013 (0.005–0.250), P < 0.001, 0.001 (0–0.006), P < 0.001, and 0.02 (0.008–0.055), P = 0.019; respectively]. The sensitivity, specificity, and area under curve of of C-KIT were (48.7%, 100%, 0.855; respectively, P = 0.001), and that of TET1 were (63.4%, 100%, 0.897; respectively, P = 0.001), while that of TET2 were (56.8%, 100%, 0.766; respectively, P = 0.019). When combining the three markers, the sensitivity was 77.5%, however it reached the highest sensitivity (78.6%) and specificity (100%) when combining both c-KIT + TET1 together for the diagnosis of AML. C-KIT overexpression associated with shorter DFS (P = 0.05) and increased incidence of relapse (P = 0.019). Lymph nodes involvement [HR = 2.200, P = 0.005] is an independent risk factor for shorter OS rate of AML patients. Increased BM blast % [HR = 7.768, P = 0.002], and FLT3-ITD mutation [HR = 2.989, P = 0.032] are independent risk factors for shorter DSF rate of the patients. Conclusion C-KIT, TET1, and TET2 could be used as possible useful biomarkers for the diagnosis of AML.

Can O-GIcNAc Transferase (OGT) Complex Be Used as a Target for the Treatment of Hematological Malignancies?

“…The interaction between OGT and TET proteins does not appear to regulate the expression of TET and its enzymatic activity [112], but it is able to recruit OGT to chromatin and subsequently cause O-GlcNAcylation of histones to regulate gene expression [58]. It is reported that the loss of function of TET2 is observed for 10-20% of patients with MDS/myeloproliferative neoplasm (MPN) [115], 40-50% of patients with CMML, and 10-20% of patients with AML [116], and this confirms that TET2 mutations are associated with poor outcome in intermediate risk AML [117]. In addition, the deletion of TET2 has been observed for patients with malignant lymphoma [118], and decreased levels of 5-hmC and increased levels of 5-mC have been observed for patients with TET2 mutations in lymphoma, AML, chronic myelomonocytic leukemia (CMML), and MDS [119].…”

Emerging DNA Methylome Targets in FLT3-ITD-Positive Acute Myeloid Leukemia: Combination Therapy with Clinically Approved FLT3 Inhibitors

“…Especially in AML with MLL-fusion proteins, TET1 overexpression has been observed [ 145 ]. TET1 exerts an oncogenic role in AML as it upregulates the expression of oncogenes including HOXA9 , MEIS1 , and PBX3 [ 145 ] and downregulates the tumor suppressor targets such as miR-22 [ 146 ].…”

“…TET2 mutations are associated with reduced 5hmC levels, increased DNA methylation, and therefore increased epigenetic silencing [ 152 ]. TET2 controls the self-renewal of HSCs; hence, its loss in mouse model resulted in expansion of stem cells with increased repopulation ability [ 138 , 146 ]. Consequently, TET2 mutations in HSCs leads to shift into pre-leukemic state which disrupts the ability of HSCs to differentiate into mature blood cells.…”

c-Kit Receptors as a Therapeutic Target in Cancer: Current Insights

“…31,123,124 Accordingly, it was found that c-KIT is associated significantly with poor survival, increased incidence of relapse, and unfavorable outcomes of AML patients, especially in those with CBF-AML. 31,125,126 Moreover, it had been reported that c-KIT exon 17 mutations are associated significantly with worse outcomes in adult de novo AML patients with RUNX1-RUNX1T1. [127][128][129] Genetic markers underlying AML carcinogenesis are considered to be useful prognostic markers, and they could be potential therapeutic targets for AML.…”