Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia
Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
|
| _version_ | 1797112008180498432 |
|---|---|
| author | Rastogi, N Gonzalez, JBM Srivastava, VK Alanazi, B Alanazi, RN Hughes, OM O'Neill, NS Gilkes, AF Ashley, N Deshpande, S Andrews, R Mead, A Rodrigues, NP Knapper, S Darley, RL Tonks, A |
| author_facet | Rastogi, N Gonzalez, JBM Srivastava, VK Alanazi, B Alanazi, RN Hughes, OM O'Neill, NS Gilkes, AF Ashley, N Deshpande, S Andrews, R Mead, A Rodrigues, NP Knapper, S Darley, RL Tonks, A |
| author_sort | Rastogi, N |
| collection | OXFORD |
| description | Nuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML. |
| first_indexed | 2024-03-07T08:18:21Z |
| format | Journal article |
| id | oxford-uuid:3639bd07-c563-4c4c-b5d9-9b24593ea334 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:18:21Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:3639bd07-c563-4c4c-b5d9-9b24593ea3342024-01-16T14:53:05ZNuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3639bd07-c563-4c4c-b5d9-9b24593ea334EnglishSymplectic ElementsSpringer Nature2022Rastogi, NGonzalez, JBMSrivastava, VKAlanazi, BAlanazi, RNHughes, OMO'Neill, NSGilkes, AFAshley, NDeshpande, SAndrews, RMead, ARodrigues, NPKnapper, SDarley, RLTonks, ANuclear factor I-C (NFIC) belongs to a family of NFI transcription factors that binds to DNA through CAATT-boxes and are involved in cellular differentiation and stem cell maintenance. Here we show NFIC protein is significantly overexpressed in 69% of acute myeloid leukemia patients. Examination of the functional consequences of NFIC overexpression in HSPCs showed that this protein promoted monocytic differentiation. Single-cell RNA sequencing analysis further demonstrated that NFIC overexpressing monocytes had increased expression of growth and survival genes. In contrast, depletion of NFIC through shRNA decreased cell growth, increased cell cycle arrest and apoptosis in AML cell lines and AML patient blasts. Further, in AML cell lines (THP-1), bulk RNA sequencing of NFIC knockdown led to downregulation of genes involved in cell survival and oncogenic signaling pathways including mixed lineage leukemia-1 (MLL-1). Lastly, we show that NFIC knockdown in an ex vivo mouse MLL::AF9 pre-leukemic stem cell model, decreased their growth and colony formation and increased expression of myeloid differentiation markers Gr1 and Mac1. Collectively, our results suggest that NFIC is an important transcription factor in myeloid differentiation as well as AML cell survival and is a potential therapeutic target in AML. |
| spellingShingle | Rastogi, N Gonzalez, JBM Srivastava, VK Alanazi, B Alanazi, RN Hughes, OM O'Neill, NS Gilkes, AF Ashley, N Deshpande, S Andrews, R Mead, A Rodrigues, NP Knapper, S Darley, RL Tonks, A Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title | Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title_full | Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title_fullStr | Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title_full_unstemmed | Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title_short | Nuclear factor I-C overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| title_sort | nuclear factor i c overexpression promotes monocytic development and cell survival in acute myeloid leukemia |
| work_keys_str_mv | AT rastogin nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT gonzalezjbm nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT srivastavavk nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT alanazib nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT alanazirn nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT hughesom nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT oneillns nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT gilkesaf nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT ashleyn nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT deshpandes nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT andrewsr nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT meada nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT rodriguesnp nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT knappers nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT darleyrl nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia AT tonksa nuclearfactoricoverexpressionpromotesmonocyticdevelopmentandcellsurvivalinacutemyeloidleukemia |