Acute leukemia is a malignant clonal disorder originating in HSCs characterized by the proliferation of blast cells in the B.M, replacing the normal B.M cells. It has two major forms: ALL and AML (11). The TET1 gene is an epigenetic regulator of DNA demethylation regulating gene expression by establishing transcriptional activation or suppression in a tissue- and gene-specific manner. Besides, TET1 regulates cell fate decisions; therefore, dysregulation contributes to tumorigenesis. The TET1 plays dual roles in tumorigenesis either, being an oncogene or a tumor suppressor gene depending on the cellular context, other epigenetic regulators, and different interacting partners that are cell type-specific (8).
In our study, we reported a significant TET1 gene upregulation in 62.2% of the studied AML patients. The significant high TET1 level was found in 66.7% of patients with AML, NOS; 66.7%, 83.3%, and 61.9% of AML without maturation, AML with maturation, and AML with monocytic differentiation groups of patients, respectively. These results were in contrast with Jiang et al. 2017 (13) concerning TET1 expression in AML with monocytic differentiation group of patients, and this might be because they included only AML patients aged more than 14 at diagnosis.
Regarding AML with recurrent cytogenetic abnormalities in our study, 100% of patients with AML carrying t(8;21) showed TET1 downregulation with no difference in TET1 expression level among AML patients with t(15;17), conflicting with Jiang et al. 2017 (13), (14), (9), respectively. The discrepancy between studies could be the result of the small number of patients in our study.
Clinically, we found that TET1 gene expression was significantly decreased in patients with enlarged lymph nodes, which was in agreement with Cimmino et al. 2015 (16) study.
Our study demonstrated that a higher percent of blast cells in P.B was significantly associated with patients who expressed higher levels of TET1 gene compared to cases of the downregulated gene. No significant correlation between TET1 level and the blast percentage in B.M, age, sex, WBCs count, hemoglobin level, platelet counts in concordance with Wang et al. 2018 (17) study; however, Kim et al. 2017 (18) declared that WBCs count, hemoglobin level, and platelets count were all decreased with TET1 upregulation. This disagreement between studies might be caused by the inclusion of animal P.B and B.M samples by Kim et al. 2017 (18) study.
These findings supported the role of TET1 in leukemogenesis. High TET1 expression in AML patients attributed to activation of cancer-specific oncogenic mechanisms and correlated with the upregulation of RNA transport and ribosome biogenesis pathways initiating leukemia (19), (3), (20).
As for ALL, our study found that in B lymphoblastic leukemia/lymphoma patients, the TET1 gene was significantly downregulated in concordance with An, Rao, and Ko 2017 (21), W. Li and Xu 2019 (22), and Zhao et al. 2015 (23) who reported that TET1 gene downregulation in HSCs and progenitor cells provided a basis for DNA damage. Low TET1 gene expression caused widespread genetic and epigenetic changes in HSCs, which accumulated with the continuous proliferation and blocked the B cell maturation, predisposing to develop leukemia of B cell origin and revealing its tumor suppressor role in B lymphoblastic leukemia/lymphoma (24).
On the other hand, in our study, all B lymphoblastic leukemia/lymphoma patients carrying MLL gene rearrangements showed TET1 upregulation. Similarly, several studies such as H. Huang et al. 2013(29) and Ko et al. 2015(25) reported that MLL fusion proteins directly increased TET1 expression, which promoted cell proliferation and inhibited cell differentiation and apoptosis, leading to cell transformation and leukemogenesis. Besides, Cimmino et al. 2015(16), and Kim et al. 2017(18) defined the TET1 gene as a fusion partner of the MLL gene in cases of acute leukemia bearing t(10;11)(q22;q23) producing the MLL – TET1 (MT1) fusion protein, which resulted in imbalance in the TET1-mediated DNA demethylation, as well as inhibited cellular differentiation thus participating in leukemogenesis. However, the upregulation of the TET1 gene in MLL rearranged leukemia patients in our study was not significant may be due to the small number of B-ALL patients carrying MLL gene rearrangement. We found no significant difference in TET1 expression level among B lymphoblastic leukemia/lymphoma patients carrying the BCR-ABL fusion gene. Correlation with this cytogenetic marker could not be found in previous studies.
As for T lymphoblastic leukemia/lymphoma patients, this study reported a significantly high expression of the TET1 gene in all patients, in agreement with Jiang et al. 2017 (13) who found that high TET1 expression in T lymphoblastic leukemia/lymphoma patients correlated with the upregulation of RNA transport driving tumor genesis.
Another mechanism was indicated by Sahin et al. 2016 (26) and (Bamezai et al. 2021) (27) that poly (ADP-ribose) polymerase enzyme (PARP), an enzyme essential for single-strand DNA damage repair, positively influenced the TET1 expression causing its hypomethylation and, therefore, increased expression of TET1 in T lymphoblastic leukemia/lymphoma. High expression of TET1 promoted the growth of T-ALL cells by regulating the expression of DNA repair genes and by protecting the genome from damage through maintaining expression of factors required for growth and genomic integrity of T-ALL cells, indicating that high TET1 enzymatic activity was advantageous for the leukemic growth and chemoresistance of T-ALL cells.
All together, these findings support the opposing roles of TET1 gene in ALL, being a tumor suppressor in B lymphoblastic leukemia/lymphoma (23) and an oncogene in T lymphoblastic leukemia/lymphoma (28). Besides, we demonstrated that a higher percent of blast cells in P.B and B.M was significantly associated with patients who expressed lower levels of TET1 gene compared to cases of the upregulated gene. However, H. Huang et al. 2013 (29) reported that decreased TET1 expression reduced the proportion of blast cells in both B.M and P.B and was associated with minimal leukemia cell infiltration. Whereas Zhao et al. 2015 (23) found no significant correlation between TET1 expression and the percentage of B.M blasts. The discrepancy between the studies may be due to that they included animal P.B and B.M samples.
There was no significant correlation between TET1 expression and age, sex, WBCs count, hemoglobin level, and platelet counts, concordant with what stated in Wang et al. 2018 (17).
The TET1 expression level was significantly lower in patients with generalized lymphadenopathy and fever, agreeing with Cimmino et al. 2015 (16) indicating the role of TET1 downregulation in pathogenesis of ALL.
Other than these previous correlations, no correlation was found between TET1 expression levels and other laboratory and clinical data.