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BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.


Type

Article

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Authors

Wyspiańska, BS 
Bannister, AJ 
Godfrey, A 

Abstract

Small molecule inhibition of the BET family of proteins, which bind acetylated lysines within histones, has been shown to have a marked therapeutic benefit in pre-clinical models of mixed lineage leukemia (MLL) fusion protein-driven leukemias. Here, we report that I-BET151, a highly specific BET family bromodomain inhibitor, leads to growth inhibition in a human erythroleukemic (HEL) cell line as well as in erythroid precursors isolated from polycythemia vera patients. One of the genes most highly downregulated by I-BET151 was LMO2, an important oncogenic regulator of hematopoietic stem cell development and erythropoiesis. We previously reported that LMO2 transcription is dependent upon Janus kinase 2 (JAK2) kinase activity in HEL cells. Here, we show that the transcriptional changes induced by a JAK2 inhibitor (TG101209) and I-BET151 in HEL cells are significantly over-lapping, suggesting a common pathway of action. We generated JAK2 inhibitor resistant HEL cells and showed that these retain sensitivity to I-BET151. These data highlight I-BET151 as a potential alternative treatment against myeloproliferative neoplasms driven by constitutively active JAK2 kinase.

Description

Keywords

Cell Line, Tumor, Chromatin Immunoprecipitation, Hematologic Neoplasms, Humans, Janus Kinase 2, Myeloproliferative Disorders, Oncogene Proteins, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction

Journal Title

Leukemia

Conference Name

Journal ISSN

0887-6924
1476-5551

Volume Title

28

Publisher

Springer Science and Business Media LLC
Sponsorship
Leukaemia & Lymphoma Research (12029)
Wellcome Trust (097922/Z/11/Z)
Medical Research Council (MC_PC_12009)
Leukemia & Lymphoma Society (7001-12)
Cancer Research Uk (None)
Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
National Centre for the Replacement Refinement and Reduction of Animals in Research (G0900729/1)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (092096/Z/10/Z)
Wellcome Trust (079249/Z/06/H)
The Kouzarides laboratory was supported by Cancer Research UK, Leukaemia and Lymphoma Research, GlaxoSmithKline and BBSRC. The Green laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Gottgens laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. The Huntly laboratory was supported by Cancer Research UK and Leukaemia and Lymphoma Research, UK. M. A Dawson, E Cannizzaro and M. Wiese are funded by the Wellcome Trust Beit Fellowship.