Journal
NATURE
Volume 461, Issue 7265, Pages 819-U79Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature08448
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Funding
- General Sir John Monash Foundation
- Cambridge Commonwealth Trust
- Raymond and Beverly Sackler
- UK Leukaemia Research Fund
- Wellcome Trust
- Leukemia & Lymphoma Society of America
- National Institute for Health Research Cambridge Biomedical Research Centre
- Leukaemia Research Fund
- Cancer Research UK
- Medical Research Council
- 6th Research Framework Programme of the European Union ( Epitron, HEROIC and SMARTER).
- MRC [G0800784] Funding Source: UKRI
- Medical Research Council [G0800784, G0800784B, G0300723B] Funding Source: researchfish
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Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies(1-6). JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1 alpha (HP1 alpha), but not HP1 beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1a at the same site. These results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia(1-9).
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