JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin

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Abstract
JAK2 is a non-receptor tyrosine kinase that regulates diverse cellular processes by inducing cytoplasmic signalling cascades. Dawson et al. now report a previously unknown nuclear function for JAK2. Tyrosine phosphorylation of histone H3 by JAK2 can lead to disruption of HP1 α binding to chromatin and changes in gene expression. This finding is of particular interest because JAK2 inhibitors are in clinical trials for the treatment of myeloid leukaemias in which JAK2 is dysregulated. The activation of Janus kinase 2 (JAK2), a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades, is a frequent event in haematological malignancies. Here, human JAK2 is shown to be present in the nucleus of haematopoietic cells, where it directly phosphorylates Tyr 41 on histone H3, thus preventing the binding of heterochromatin protein Iα. Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies1,2,3,4,5,6. 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 1α (HP1α), but not HP1β, 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 HP1α 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 leukaemia1,2,3,4,5,6,7,8,9.