Mechanisms of FLT3 transcriptional deregulation in acute leukemias
| Subtype . | Experimental model . | Genetic alteration . | Mechanism . | References . |
|---|---|---|---|---|
| B-cell precursor acute lymphoblastic leukemia (BCP-ALL) | BCP-ALL patient samples (n = 1418); GM12878 and NALM-6 cell lines | 13q12.2 deletion | 13q12.2 deletions disrupt chromatin structure and change promoter-enhancer interactions in this region (enhancer hijacking), leading to increased expression of the FLT3 gene | 1 |
| Pro-B-cell lines; bone marrow progenitors; Pax5−/− mice; and case report | PAX5 deletion | It was already demonstrated that Pax5 represses Flt3 transcription in B-cell progenitors, and that Pax5-deficient pro-B cells express abundant Flt3 levels. Based on that, it has been suggested that PAX5 heterozygous deletion in B-cell acute leukemia could be related to FLT3 overexpression | 16,17 | |
| T-cell acute lymphoblastic leukemia (T-ALL) | T-ALL patient samples (n = 60); human leukemia xenograft model; and Jurkat cell line | Loss-of-function alterations of SUZ12, EED, and EZH2 | PRC2 inactivation, due to loss-of-function alterations of SUZ12, EDD, and EZH2, leads to the loss of H3K27me3 in FLT3 promoter region resulting in increased FLT3 expression | 18 |
| Acute myeloid leukemia (AML) | AML patients (TCGA, n = 158); and leukemia stem cells from AML mouse model | DNMT1 haploinsufficient | DNMT1 haploinsufficiency may lead to hypomethylation of FLT3 promoter region, which results in its increased expression | 14 |
| MV4-11, K562, and THP1 human leukemia cell lines | Loss of MSI2 | FLT3 expression can also be regulated by a post-transcriptional mechanism through the MSI2 protein, which physically binds to FLT3 messenger RNA transcripts. In case of genetic loss of MSI2, negative regulation of FLT3 expression is observed, and impaired leukemic growth | 19 | |
| MV4-11 and THP-1 cell lines; THP-1 xenograft murine model | Inhibition of PRMT5 | The PRMT5-Sp1 transcription repressor complex is capable of silencing miR-29b via dimethylation of histone 4 arginine residue H4R3. As a result, an increase in Sp1 is observed, as it is a bona fide target of miR-29b. This event in turn leads to the activation of FLT3 transcription. Thus, the inhibition of PRMT5 can result in a significant increase in the expression of miR-29b and consequent suppression of Sp1 and FLT3 | 20 | |
| Murine-cultured model and bone marrow samples from 104 AML patients | CEBPA biallelic mutations | Together, HOXA9, MEIS1, MYB, and C/EBPα are important elements in FLT3 regulation. In this way, it was observed that CEBPA bi-allelic mutations, mainly in the absence of FLT3 activating mutations, are associated with reduced levels of FLT3 transcript | 21 |
| Subtype . | Experimental model . | Genetic alteration . | Mechanism . | References . |
|---|---|---|---|---|
| B-cell precursor acute lymphoblastic leukemia (BCP-ALL) | BCP-ALL patient samples (n = 1418); GM12878 and NALM-6 cell lines | 13q12.2 deletion | 13q12.2 deletions disrupt chromatin structure and change promoter-enhancer interactions in this region (enhancer hijacking), leading to increased expression of the FLT3 gene | 1 |
| Pro-B-cell lines; bone marrow progenitors; Pax5−/− mice; and case report | PAX5 deletion | It was already demonstrated that Pax5 represses Flt3 transcription in B-cell progenitors, and that Pax5-deficient pro-B cells express abundant Flt3 levels. Based on that, it has been suggested that PAX5 heterozygous deletion in B-cell acute leukemia could be related to FLT3 overexpression | 16,17 | |
| T-cell acute lymphoblastic leukemia (T-ALL) | T-ALL patient samples (n = 60); human leukemia xenograft model; and Jurkat cell line | Loss-of-function alterations of SUZ12, EED, and EZH2 | PRC2 inactivation, due to loss-of-function alterations of SUZ12, EDD, and EZH2, leads to the loss of H3K27me3 in FLT3 promoter region resulting in increased FLT3 expression | 18 |
| Acute myeloid leukemia (AML) | AML patients (TCGA, n = 158); and leukemia stem cells from AML mouse model | DNMT1 haploinsufficient | DNMT1 haploinsufficiency may lead to hypomethylation of FLT3 promoter region, which results in its increased expression | 14 |
| MV4-11, K562, and THP1 human leukemia cell lines | Loss of MSI2 | FLT3 expression can also be regulated by a post-transcriptional mechanism through the MSI2 protein, which physically binds to FLT3 messenger RNA transcripts. In case of genetic loss of MSI2, negative regulation of FLT3 expression is observed, and impaired leukemic growth | 19 | |
| MV4-11 and THP-1 cell lines; THP-1 xenograft murine model | Inhibition of PRMT5 | The PRMT5-Sp1 transcription repressor complex is capable of silencing miR-29b via dimethylation of histone 4 arginine residue H4R3. As a result, an increase in Sp1 is observed, as it is a bona fide target of miR-29b. This event in turn leads to the activation of FLT3 transcription. Thus, the inhibition of PRMT5 can result in a significant increase in the expression of miR-29b and consequent suppression of Sp1 and FLT3 | 20 | |
| Murine-cultured model and bone marrow samples from 104 AML patients | CEBPA biallelic mutations | Together, HOXA9, MEIS1, MYB, and C/EBPα are important elements in FLT3 regulation. In this way, it was observed that CEBPA bi-allelic mutations, mainly in the absence of FLT3 activating mutations, are associated with reduced levels of FLT3 transcript | 21 |