BET protein inhibition shows efficacy against JAK2V617F-driven neoplasms.
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.
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
B S
BS
Wyspiańska
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
A J
AJ
Bannister
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
I
I
Barbieri
1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
J
J
Nangalia
1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
A
A
Godfrey
Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
F J
FJ
Calero-Nieto
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
S
S
Robson
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
I
I
Rioja
1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
J
J
Li
1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
M
M
Wiese
1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
E
E
Cannizzaro
1] Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK [2] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [3] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
M A
MA
Dawson
Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
B
B
Huntly
Epinova DPU, Immuno-Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Stevenage, UK.
R K
RK
Prinjha
1] Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK [2] Addenbrooke's Hospital, Department of Haematology, University of Cambridge, Cambridge, UK.
A R
AR
Green
Department of Haematology, Cambridge Institute for Medical Research and The Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
B
0000000163025705
B
Gottgens
Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, UK.
T
T
Kouzarides
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015513:Oncogene Proteins; D053614:Janus Kinase 2