BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma
Abstract Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interferen...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-07-01
|
| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-022-00704-7 |
| _version_ | 1811287102793449472 |
|---|---|
| author | Ellen Weisberg Basudev Chowdhury Chengcheng Meng Abigail E. Case Wei Ni Swati Garg Martin Sattler Abdel Kareem Azab Jennifer Sun Barbara Muz Dana Sanchez Anthia Toure Richard M. Stone Ilene Galinsky Eric Winer Scott Gleim Sofia Gkountela Alexia Kedves Edmund Harrington Tinya Abrams Thomas Zoller Andrea Vaupel Paul Manley Michael Faller BoYee Chung Xin Chen Philipp Busenhart Christine Stephan Keith Calkins Debora Bonenfant Claudio R. Thoma William Forrester James D. Griffin |
| author_facet | Ellen Weisberg Basudev Chowdhury Chengcheng Meng Abigail E. Case Wei Ni Swati Garg Martin Sattler Abdel Kareem Azab Jennifer Sun Barbara Muz Dana Sanchez Anthia Toure Richard M. Stone Ilene Galinsky Eric Winer Scott Gleim Sofia Gkountela Alexia Kedves Edmund Harrington Tinya Abrams Thomas Zoller Andrea Vaupel Paul Manley Michael Faller BoYee Chung Xin Chen Philipp Busenhart Christine Stephan Keith Calkins Debora Bonenfant Claudio R. Thoma William Forrester James D. Griffin |
| author_sort | Ellen Weisberg |
| collection | DOAJ |
| description | Abstract Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM. |
| first_indexed | 2024-04-13T03:13:01Z |
| format | Article |
| id | doaj.art-3c275c0fed054a4ca5adaa6cd08da2ce |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-04-13T03:13:01Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-3c275c0fed054a4ca5adaa6cd08da2ce2022-12-22T03:05:00ZengNature Publishing GroupBlood Cancer Journal2044-53852022-07-0112711010.1038/s41408-022-00704-7BRD9 degraders as chemosensitizers in acute leukemia and multiple myelomaEllen Weisberg0Basudev Chowdhury1Chengcheng Meng2Abigail E. Case3Wei Ni4Swati Garg5Martin Sattler6Abdel Kareem Azab7Jennifer Sun8Barbara Muz9Dana Sanchez10Anthia Toure11Richard M. Stone12Ilene Galinsky13Eric Winer14Scott Gleim15Sofia Gkountela16Alexia Kedves17Edmund Harrington18Tinya Abrams19Thomas Zoller20Andrea Vaupel21Paul Manley22Michael Faller23BoYee Chung24Xin Chen25Philipp Busenhart26Christine Stephan27Keith Calkins28Debora Bonenfant29Claudio R. Thoma30William Forrester31James D. Griffin32Department of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteWashington University in Saint Louis School of MedicineWashington University in Saint Louis School of MedicineWashington University in Saint Louis School of MedicineDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGNovartis Pharma AGDepartment of Medical Oncology, Dana-Farber Cancer InstituteAbstract Bromodomain-containing protein 9 (BRD9), an essential component of the SWI/SNF chromatin remodeling complex termed ncBAF, has been established as a therapeutic target in a subset of sarcomas and leukemias. Here, we used novel small molecule inhibitors and degraders along with RNA interference to assess the dependency on BRD9 in the context of diverse hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) model systems. Following depletion of BRD9 protein, AML cells undergo terminal differentiation, whereas apoptosis was more prominent in ALL and MM. RNA-seq analysis of acute leukemia and MM cells revealed both unique and common signaling pathways affected by BRD9 degradation, with common pathways including those associated with regulation of inflammation, cell adhesion, DNA repair and cell cycle progression. Degradation of BRD9 potentiated the effects of several chemotherapeutic agents and targeted therapies against AML, ALL, and MM. Our findings support further development of therapeutic targeting of BRD9, alone or combined with other agents, as a novel strategy for acute leukemias and MM.https://doi.org/10.1038/s41408-022-00704-7 |
| spellingShingle | Ellen Weisberg Basudev Chowdhury Chengcheng Meng Abigail E. Case Wei Ni Swati Garg Martin Sattler Abdel Kareem Azab Jennifer Sun Barbara Muz Dana Sanchez Anthia Toure Richard M. Stone Ilene Galinsky Eric Winer Scott Gleim Sofia Gkountela Alexia Kedves Edmund Harrington Tinya Abrams Thomas Zoller Andrea Vaupel Paul Manley Michael Faller BoYee Chung Xin Chen Philipp Busenhart Christine Stephan Keith Calkins Debora Bonenfant Claudio R. Thoma William Forrester James D. Griffin BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma Blood Cancer Journal |
| title | BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| title_full | BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| title_fullStr | BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| title_full_unstemmed | BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| title_short | BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| title_sort | brd9 degraders as chemosensitizers in acute leukemia and multiple myeloma |
| url | https://doi.org/10.1038/s41408-022-00704-7 |
| work_keys_str_mv | AT ellenweisberg brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT basudevchowdhury brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT chengchengmeng brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT abigailecase brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT weini brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT swatigarg brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT martinsattler brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT abdelkareemazab brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT jennifersun brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT barbaramuz brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT danasanchez brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT anthiatoure brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT richardmstone brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT ilenegalinsky brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT ericwiner brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT scottgleim brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT sofiagkountela brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT alexiakedves brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT edmundharrington brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT tinyaabrams brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT thomaszoller brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT andreavaupel brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT paulmanley brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT michaelfaller brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT boyeechung brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT xinchen brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT philippbusenhart brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT christinestephan brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT keithcalkins brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT deborabonenfant brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT claudiorthoma brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT williamforrester brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma AT jamesdgriffin brd9degradersaschemosensitizersinacuteleukemiaandmultiplemyeloma |