Myeloproliferation in mice lacking a lipoxygenase (KO) leads to bigger spleens.

Suppressing the action of lipoxygenases may reduce “bad cholesterol” deposition and inflammation in the arteries and thereby prevent heart attacks. But doing so might inadvertently cause leukemia, warn Middleton et al. (page 2529).

While studying atherosclerosis (artery hardening) using 12/15-lipoxygenase (12/15-LO) knock-out mice, Ellen Puré's team made an unexpected discovery: the spleens of all the mice were enlarged. Closer inspection of the spleens revealed a distinct increase in the myeloid cell population—a feature indicative of myeloid proliferative disease (MPD). Consistent with this leukemia, lymph nodes displayed an abnormal excess of cells, and the leukocyte count of peripheral blood was markedly increased.

12/15-LO−/− splenocytes showed increased levels of the Bcl-2 oncoprotein and reduced nuclear accumulation of the ICSBP transcription factor, which represses Bcl-2. Exactly how loss of 12/15-LO leads to loss of nuclear localization of ICSBP, however, is yet to be determined.

The mice were slightly more likely to die early, but the majority had no obvious external symptoms even up to one year of age. The protracted, chronic phase of the most common form of human MPD, chronic myelogenous leukemia (CML), is also usually asymptomatic. As a result, CML often goes undiagnosed in the chronic phase and becomes apparent only when the disease progresses to the more life-threatening “blast” phase (when the number of immature white blood cells is extremely high).

Many existing mouse models of CML show rapid progression of the disease and are thus relevant for studying the blast crisis phase only. But the 12/15-LO−/− mice are a potentially valuable model system for studying the entire chronic phase as well as disease progression.

12/15-LO−/− mice have long been used in the study of atherosclerosis, but other groups possibly overlooked the enlarged spleens, says Puré. Even more astounding is that, although reduced activity of human lipoxygenases had been reported in human leukemia, its direct involvement in the disease had not been studied.

Now that Middleton and colleagues provide stronger evidence for the link between MPD and 12/15-LO, researchers and drug companies investigating the antiatherosclerotic potential of suppressing 12/15-LO should certainly be on the lookout for features of leukemia.