Examples of alterations of enhancers in hematopoietic malignancies
| Disease . | Alteration event . | Effect on disease . | Reference . |
|---|---|---|---|
| AML | De novo RARA enhancer | Promotes sensitivity to potent RARA antagonists | 35 |
| B-cell lymphomas, multiple myeloma | t(8;14) | Myc driven by IgH enhancer | 38-42 |
| T-ALL | t(1;14) | TAL1 driven by TCR enhancers | 44 |
| T-ALL | Deletions | TAL1 driven by SIL enhancer | 45-46 |
| AML | t(3;3), inv(3) | EVI1 driven by GATA2 enhancer, hemizygous loss of expression of GATA2 | 48-49,51 |
| T-ALL | Duplication at 8q24 | Copy-number amplification of a NOTCH1-bound enhancer that drives MYC expression | 52 |
| AML | Copy-number amplifications 1.7 Mb downstream of MYC | Copy-number amplification of MYC enhancers | 53-55 |
| T-ALL | Focal indels 8 kb upstream of TAL1 | Creation of de novo MYB binding site, generating a superenhancer that drives TAL1 expression | 60 |
| T-ALL | SNP 4 kb upstream of the LMO1 transcription start site | Creation of de novo MYB binding site, generating an enhancer that drives LMO1 expression | 61 |
| CLL | Mutations at 9p13 | Disruption of enhancer that regulates PAX5 | 63 |
| CLL | Mutations at 15q15.1 | Disruption of RELA enhancer that regulates BMF, leading to increased risk of CLL development | 16,69 |
| T-ALL | Aberrant NOTCH1 activity | NOTCH1 binds to an enhancer to drive LUNAR1 transcription. LUNAR1 is required for IGFR1 expression and T-ALL survival | 70 |
| AML | DNMT3A R882H mutations | Mutant DNTM3A leads to loss of methylation at broad enhancers, activation of self-renewal gene programs | 72-74 |
| AML | TET2 mutations | Mutant TET2 leads to hypermethylated DNA at enhancers, resulting in suppression of gene expression | 77 |
| AML | Cohesin complex mutations | Impaired differentiation, increased self-renewal in hematopoietic stem and progenitor cells | 78-81 |
| T-ALL | CTCF binding site deletions | Disruption of TAD insulation surrounding TAL1 and LMO2 genes, leading to aberrant enhancer activation of these genes | 83 |
| Disease . | Alteration event . | Effect on disease . | Reference . |
|---|---|---|---|
| AML | De novo RARA enhancer | Promotes sensitivity to potent RARA antagonists | 35 |
| B-cell lymphomas, multiple myeloma | t(8;14) | Myc driven by IgH enhancer | 38-42 |
| T-ALL | t(1;14) | TAL1 driven by TCR enhancers | 44 |
| T-ALL | Deletions | TAL1 driven by SIL enhancer | 45-46 |
| AML | t(3;3), inv(3) | EVI1 driven by GATA2 enhancer, hemizygous loss of expression of GATA2 | 48-49,51 |
| T-ALL | Duplication at 8q24 | Copy-number amplification of a NOTCH1-bound enhancer that drives MYC expression | 52 |
| AML | Copy-number amplifications 1.7 Mb downstream of MYC | Copy-number amplification of MYC enhancers | 53-55 |
| T-ALL | Focal indels 8 kb upstream of TAL1 | Creation of de novo MYB binding site, generating a superenhancer that drives TAL1 expression | 60 |
| T-ALL | SNP 4 kb upstream of the LMO1 transcription start site | Creation of de novo MYB binding site, generating an enhancer that drives LMO1 expression | 61 |
| CLL | Mutations at 9p13 | Disruption of enhancer that regulates PAX5 | 63 |
| CLL | Mutations at 15q15.1 | Disruption of RELA enhancer that regulates BMF, leading to increased risk of CLL development | 16,69 |
| T-ALL | Aberrant NOTCH1 activity | NOTCH1 binds to an enhancer to drive LUNAR1 transcription. LUNAR1 is required for IGFR1 expression and T-ALL survival | 70 |
| AML | DNMT3A R882H mutations | Mutant DNTM3A leads to loss of methylation at broad enhancers, activation of self-renewal gene programs | 72-74 |
| AML | TET2 mutations | Mutant TET2 leads to hypermethylated DNA at enhancers, resulting in suppression of gene expression | 77 |
| AML | Cohesin complex mutations | Impaired differentiation, increased self-renewal in hematopoietic stem and progenitor cells | 78-81 |
| T-ALL | CTCF binding site deletions | Disruption of TAD insulation surrounding TAL1 and LMO2 genes, leading to aberrant enhancer activation of these genes | 83 |