CXCR4-independent rescue of the myeloproliferative defect of the Gata1 ^low myelofibrosis mouse model by aplidin®

The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms has prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases. However, the results of the first clinical trials with JAK2 inhibitors are not as promising as expected, prompting a search for additional drugable targets to treat these disorders. In this paper, we used the hypomorphic Gata1^low mouse model of primary myelofibrosis (PMF), the most severe of these neoplasms, to test the hypothesis that defective marrow hemopoiesis and development of extramedullary hematopoiesis in myelofibrosis is due to insufficient p27 ^Kip1 activity and is treatable by Aplidin®, a cyclic depsipeptide that activates p27^Kip1 in several cancer cells. Aplidin® restored expression of Gata1 and p27^Kip1 in Gata1^low hematopoietic cells, proliferation of marrow progenitor cells in vitro and maturation of megakaryocytes in vivo (reducing TGF-β/VEGF levels released in the microenvironment by immature Gata1^low megakaryocytes). Microvessel density, fibrosis, bone growth, and marrow cellularity were normal in Aplidin®-treated mice and extramedullary hematopoiesis did not develop in liver although CXCR4 expression in Gata1^low progenitor cells remained low. These results indicate that Aplidin® effectively alters the natural history of myelofibrosis in Gata1^low mice and suggest this drug as candidate for clinical evaluation in PMF.