Tumor Suppressor, Nore1a (Rassf5), Is An Icsbp-Dependent Inhibitor Of Aberrant Stress Granulopoiesis

Within the innate immune system, emergency (stress) granulopoiesis serves the specific and essential function of periodic granulocyte production in response to an infectious or inflammatory challenge. Emergency granulopoiesis occurs in four phases (immediate release of mature granulocytes from the bone marrow, expansion of the common granulocyte/monocyte progenitor pool, accelerated differentiation, and termination of the response) and requires IL1β, an IL1β-dependent increase in G-CSF and the transcription factors Stat3 and C/EPBβ. Our group has previously shown that interferon consensus sequence binding protein (Icsbp) is required for the termination of emergency granulopoiesis. Icsbp deficiency is associated with increased and sustained production of Fap1 and Gas2, aberrantly sustained granulocytosis and promotion of myeloid leukemia. We have identified a novel Icsbp target gene, NORE1A (RASSF5), that is likewise required for the termination of emergency granulopoiesis. Nore1A is a tumor suppressor that is down-regulated in many human cancers. We found that Icsbp acts as a NORE1A transcriptional activator and that Nore1A expression is decreased in bone marrow-derived myeloid progenitor cells from ICSBP -/- mice compared to wild-type (WT), and does not appropriately increase during ex vivo differentiation with G-CSF or IL1β. In cell culture, ICSBP -/- murine bone marrow cells were resistant to intrinsic or Fas-induced apoptosis compared to WT. However, transduction with a Nore1A expression vector rescued Fas-induced apoptosis in ICSBP -/- murine bone marrow-derived myeloid progenitor cells, associated with activation of the pro-apoptotic Mst1 kinase. We injected WT or NORE1 -/- mice intraperitoneally every 4 weeks with an ovalbumin/alum mixture (to stimulate emergency granulopoiesis) or saline control. NORE1 -/- mice demonstrated aberrantly exaggerated granulocytosis in response to repeated cycles of ovalbumin/alum stimulation compared to WT mice. NORE1 -/- mice also demonstrated a tendency to develop myeloid leukemia, even in the absence of overt immune stimulation. These findings suggest that Nore1A inhibits aberrant stress granulopoiesis by promoting apoptosis of myeloid cells in an Icsbp-dependent fashion. Our data implicate Nore1A deficiency in the deregulation of granulopoiesis and promotion of leukemogenesis that accompanies clinical scenarios associated with decreased Icsbp activity, such as human chronic myeloid leukemia.