BET bromodomain proteins (e.g. BRD4) are attractive therapeutic targets for many haematopoietic malignancies. Here we find that myc-driven pre-B-/B-cell leukaemia/lymphomas are highly sensitive to the prototypical BET bromodomain inhibitor JQ1. Unexpectedly, their normal untransformed counterparts - B lymphocytes - are also readily killed by JQ1, both in vitro and in vivo. Apart from B lymphocytes, some other haematopoietic subsets, like immature T lymphocytes, are also highly sensitive to JQ1 treatment. In vitro cell survival assays with diverse haematopoietic cells lacking one or more Bcl‑2 family member reveal the killing induced by JQ1 is through Bax/Bak-mediated apoptosis. This is confirmed by in vivo JQ1 treatment as Bax/Bak-deficient hematopoietic cells, unlike their wild-type counterparts, are largely unaffected. Unlike the induction of apoptosis in the more mature haematopoietic cell types, JQ1 principally inhibited the proliferation of hematopoietic stem cells.
Taken together, our data indicates that a major mechanism that the BET bromodomain inhibitors act is through induction of Bax/Bak-mediated apoptosis and has significant implications for why such therapy might fail. Moreover, the impact of these agents on normal blood cells suggest that simple blood counts may be useful for monitoring patients on treatment with drugs such as JQ1,