JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin

JAK2 signalling is implicated in various biological processes, including cell cycle progression, apoptosis, mitotic recombination, genetic instability and alteration of heterochromatin (10-13). The most common somatic alteration of JAK2 is [...]
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 Tyr41 (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 HP1 α 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).