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Preclinical studies on the use of a P-selectin-blocking monoclonal antibody to halt progression of myelofibrosis in the Gata1low mouse model

Published:September 30, 2022DOI:https://doi.org/10.1016/j.exphem.2022.09.004

      Highlights

      • We demonstrated that treatment with the antibody RB40.34, which targets murine P-selectin, and ruxolitinib in combination is more effective than either drug alone in rescuing the phenotype expressed by the Gata1low mouse model of myelofibrosis.
      • The two drugs in combination reduced fibrosis, bone deposition, and neoangiogenesis while restoring hematopoiesis in the bone marrow and reducing hematopoiesis and restoring the architecture of the spleen of Gata1low mice.
      • Mechanistically, the two drugs in combination may have exerted these effects by reducing the TGF-β and CXCL1 content, the two proinflammatory cytokines supposed to be the driver of fibrosis, in the bone marrow.
      • These data provide preclinical evidence that P-selectin antibodies and ruxolitinib in combination may be more effective than ruxolitinib alone to treat myelofibrosis.
      The bone marrow (BM) and spleen from patients with myelofibrosis (MF), as well as those from the Gata1low mouse model of the disease contain increased number of abnormal megakaryocytes. These cells express high levels of the adhesion receptor P-selectin on their surface, which triggers a pathologic neutrophil emperipolesis, leading to increased bioavailability of transforming growth factor-β (TGF-β) in the microenvironment and disease progression. With age, Gata1low mice develop a phenotype similar to that of patients with MF, which is the most severe of the Philadelphia-negative myeloproliferative neoplasms. We previously demonstrated that Gata1low mice lacking the P-selectin gene do not develop MF. In the current study, we tested the hypothesis that pharmacologic inhibition of P-selectin may normalize the phenotype of Gata1low mice that have already developed MF. To test this hypothesis, we have investigated the phenotype expressed by aged Gata1low mice treated with the antimouse monoclonal antibody RB40.34, alone and also in combination with ruxolitinib. The results indicated that RB40.34 in combination with ruxolitinib normalizes the phenotype of Gata1low mice with limited toxicity by reducing fibrosis and the content of TGF-β and CXCL1 (two drivers of fibrosis in this model) in the BM and spleen and by restoring hematopoiesis in the BM and the architecture of the spleen. In conclusion, we provide preclinical evidence that treatment with an antibody against P-selectin in combination with ruxolitinib may be more effective than ruxolitinib alone to treat MF in patients.
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