DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro
Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evol...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2022-11-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.1032958/full |
| _version_ | 1797988971407474688 |
|---|---|
| author | Eliza Mari Kwesi-Maliepaard Muddassir Malik Tibor van Welsem Remco van Doorn Maarten H. Vermeer Hanneke Vlaming Heinz Jacobs Fred van Leeuwen Fred van Leeuwen |
| author_facet | Eliza Mari Kwesi-Maliepaard Muddassir Malik Tibor van Welsem Remco van Doorn Maarten H. Vermeer Hanneke Vlaming Heinz Jacobs Fred van Leeuwen Fred van Leeuwen |
| author_sort | Eliza Mari Kwesi-Maliepaard |
| collection | DOAJ |
| description | Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation. |
| first_indexed | 2024-04-11T08:12:53Z |
| format | Article |
| id | doaj.art-b241d9f6d9584cc68a04b26f8668305b |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-04-11T08:12:53Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-b241d9f6d9584cc68a04b26f8668305b2022-12-22T04:35:18ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-11-011310.3389/fgene.2022.10329581032958DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitroEliza Mari Kwesi-Maliepaard0Muddassir Malik1Tibor van Welsem2Remco van Doorn3Maarten H. Vermeer4Hanneke Vlaming5Heinz Jacobs6Fred van Leeuwen7Fred van Leeuwen8Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Gene Regulation, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Gene Regulation, Netherlands Cancer Institute, Amsterdam, NetherlandsDepartment of Dermatology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Dermatology, Leiden University Medical Center, Leiden, NetherlandsDivision of Gene Regulation, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Gene Regulation, Netherlands Cancer Institute, Amsterdam, NetherlandsDepartment of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsCutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation.https://www.frontiersin.org/articles/10.3389/fgene.2022.1032958/fullDOT1LHDAChistone acetylationepigeneticscutaneous T-cell lymphoma (CTCL)histone methyl transferase (HMT) |
| spellingShingle | Eliza Mari Kwesi-Maliepaard Muddassir Malik Tibor van Welsem Remco van Doorn Maarten H. Vermeer Hanneke Vlaming Heinz Jacobs Fred van Leeuwen Fred van Leeuwen DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro Frontiers in Genetics DOT1L HDAC histone acetylation epigenetics cutaneous T-cell lymphoma (CTCL) histone methyl transferase (HMT) |
| title | DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro |
| title_full | DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro |
| title_fullStr | DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro |
| title_full_unstemmed | DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro |
| title_short | DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro |
| title_sort | dot1l inhibition does not modify the sensitivity of cutaneous t cell lymphoma to pan hdac inhibitors in vitro |
| topic | DOT1L HDAC histone acetylation epigenetics cutaneous T-cell lymphoma (CTCL) histone methyl transferase (HMT) |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.1032958/full |
| work_keys_str_mv | AT elizamarikwesimaliepaard dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT muddassirmalik dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT tiborvanwelsem dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT remcovandoorn dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT maartenhvermeer dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT hannekevlaming dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT heinzjacobs dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT fredvanleeuwen dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro AT fredvanleeuwen dot1linhibitiondoesnotmodifythesensitivityofcutaneoustcelllymphomatopanhdacinhibitorsinvitro |