The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-r...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2018
|
| _version_ | 1826286672090759168 |
|---|---|
| author | Numata, A Kwok, HS Kawasaki, A Li, J Zhou, Q-L Kerry, J Benoukraf, T Bararia, D Li, F Ballabio, E Tapia, M Deshpande, AJ Welner, RS Delwel, R Yang, H Milne, TA Taneja, R Tenen, DG |
| author_facet | Numata, A Kwok, HS Kawasaki, A Li, J Zhou, Q-L Kerry, J Benoukraf, T Bararia, D Li, F Ballabio, E Tapia, M Deshpande, AJ Welner, RS Delwel, R Yang, H Milne, TA Taneja, R Tenen, DG |
| author_sort | Numata, A |
| collection | OXFORD |
| description | Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
|
| first_indexed | 2024-03-07T01:47:13Z |
| format | Journal article |
| id | oxford-uuid:98d41837-4c9c-4e3d-80d1-9ccdc713310f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:47:13Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:98d41837-4c9c-4e3d-80d1-9ccdc713310f2022-03-27T00:09:50ZThe basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemiaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:98d41837-4c9c-4e3d-80d1-9ccdc713310fEnglishSymplectic ElementsSpringer Nature2018Numata, AKwok, HSKawasaki, ALi, JZhou, Q-LKerry, JBenoukraf, TBararia, DLi, FBallabio, ETapia, MDeshpande, AJWelner, RSDelwel, RYang, HMilne, TATaneja, RTenen, DGAcute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML. |
| spellingShingle | Numata, A Kwok, HS Kawasaki, A Li, J Zhou, Q-L Kerry, J Benoukraf, T Bararia, D Li, F Ballabio, E Tapia, M Deshpande, AJ Welner, RS Delwel, R Yang, H Milne, TA Taneja, R Tenen, DG The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title | The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title_full | The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title_fullStr | The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title_full_unstemmed | The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title_short | The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia |
| title_sort | basic helix loop helix transcription factor sharp1 is an oncogenic driver in mll af6 acute myelogenous leukemia |
| work_keys_str_mv | AT numataa thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kwokhs thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kawasakia thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT lij thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT zhouql thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kerryj thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT benoukraft thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT barariad thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT lif thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT ballabioe thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tapiam thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT deshpandeaj thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT welnerrs thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT delwelr thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT yangh thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT milneta thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tanejar thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tenendg thebasichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT numataa basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kwokhs basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kawasakia basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT lij basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT zhouql basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT kerryj basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT benoukraft basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT barariad basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT lif basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT ballabioe basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tapiam basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT deshpandeaj basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT welnerrs basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT delwelr basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT yangh basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT milneta basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tanejar basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia AT tenendg basichelixloophelixtranscriptionfactorsharp1isanoncogenicdriverinmllaf6acutemyelogenousleukemia |