FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.

Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of ß-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated ß-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of ß-catenin. At the molecular level, FoxO1 interacts with ß-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated ß-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.

Beta adrenoceptor blockade mimics effects of stress on motor activity in mice.

Reduced central noradrenergic function has been implicated as a factor in reduced behavioral activity after stress. The present studies examined the role of reduced beta adrenergic neurotransmission in mediating this effect. This was done by testing the ability of beta receptor antagonists to mimic the behavioral actions of stress. Mice were subjected to stress or given various beta antagonists and tested for swimming behavior, locomotor activity, or grooming behavior. As previously reported, stress reduced swimming and locomotor activity and increased grooming. Both the nonselective antagonist, l-propranolol, and the beta-1 selective antagonist, betaxolol, produced the same effects as stress on all three measures. A beta-2 selective antagonist, ICI 118,551, was effective only on swimming, whereas a membrane stabilizing agent, d-propranolol, was effective only on grooming behavior. The peripherally active beta-1 antagonist, atenolol, was not effective on any measure. The nonspecific dopaminergic receptor blocker, fluphenazine, reduced locomotion but tended also to reduce grooming. The results indicate that blockade of beta-1 receptors in the CNS selectively mimics the action of stress on gross motor activity in mice and, along with previous data, suggest that stress leads to a relative deficiency in central beta-1 noradrenergic neurotransmission in these animals.