Abstract

CDDO-me (methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate)is a novel antioxidant inflammation modulator that has been shown to suppress tumor-induced inflammatory processes through suppression of NF-kB and STAT3 and induce apoptosis and differentiation of human leukemic and solid tumor cells.. It has also been shown to be more potent than the parent compound, CDDO against leukemia cells. We have previously shown that administration of CDDO, when given peri-transplant, can inhibit the development of acute murine GVHD and induces cell death in proliferating but not resting lymphocytes in a mixed lymphocyte culture. We therefore next sought to determine the effect of CDDO-me administration on normal hematopoiesis in naive and myelosuppressed mice. Administration of CDDO-me (120 ug/dose BID for 7 days) to C56BL/6 mice did not significantly affect the number of T and B cells in the spleen. Unexpectedly, CDDO-me administration resulted in a significant expansion of myeloid cells in the bone marrow and spleen, predominately CD11b+Ly6CintGR1hi neutrophils. To determine if CDDO-me acted primarily on terminal stages of differentiation or at early phases on development in hematopoiesis, we performed clonogeneic assays for myeloid (CFU-GM), erythroid (BFU-E) and primitive, high proliferative potential (CFU-HPP) precursors and compared treatment with CDDO-me with rhG-CSF administration, a cytokine known to promote expansion and mobilization of hematopoietic precursors from the bone marrow. Administration of CDDO-me resulted in significant expansion of myeloid and erythroid progenitors in the spleen and blood although not to the same extent as that observed in mice receiving 2.5 ug/dose BID rhG-CSF. Unlike the mobilization seen with rhG-CSF where hematopoietic precursors were decreased in the bone marrow, CDDO-me significantly increased the number of myeloid, erythroid and CFU-HPPs in the marrow. Administration of CDDO-me prior to myelosuppression with sublethal total body irradiation also resulted in significant increase of spleen cellularity after 8 days recovery due to significant expansion of myeloid cells as well as increases in B cells. However, CDDO-me did not significantly impact hematopoietic recovery compared to vehicle control treated animals when CDDO-me was given to mice following sublethal total body irradiation. These results suggest that CDDO-me can expand early hematopoietic precursors in mice, resulting in radioprotection. Stimulation of myelopoiesis in vivo by CDDO-me can be accounted for, in part, by a significant increase in circulating G-CSF levels in treated animals. However, the retention of hematopoietic precursors in the bone marrow of mice that received CDDO-me but not rhG-CSF suggest additional mechanisms are involved. These results demonstrate that CDDO-me significantly affects normal hematopoietic cells including precursor populations in vivo and can promote granulopoiesis predominately in non-irradiated mice.

Disclosures: Meyer:Reata Pharmaceuticals, Inc: Employment. Murphy:Reata Pharmaceuticals, Inc.: Research Funding.

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