CXCR4-independent rescue of the myeloproliferative defect of the gata1low myelofibrosis mouse model by Aplidin

• Published in: Journal of cellular physiology Vol. 225; no. 2; pp. 490 - 499
• Main Authors: Verrucci, Maria, Pancrazzi, Alessandro, Aracil, Miguel, Martelli, Fabrizio, Guglielmelli, Paola, Zingariello, Maria, Ghinassi, Barbara, D'Amore, Emanuela, Jimeno, José, Vannucchi, Alessandro M., Migliaccio, Anna Rita
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.11.2010; Wiley Subscription Services, Inc
• Subjects: Age Distribution; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Aplidin; Bone density; Bone growth; Bone Marrow Cells; Cell proliferation; Cells (biology); Clinical trials; CXCR4 protein; Cyclin-dependent kinase inhibitor p27; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Depsipeptides - administration & dosage; Depsipeptides - therapeutic use; Dose-Response Relationship, Drug; Drug Administration Schedule; Fibrosis; GATA-1 protein; GATA1 Transcription Factor - genetics; Gene Expression Regulation - drug effects; Hematopoiesis; Hematopoietic stem cells; Hemopoiesis; Hepatocytes; In vivo methods and tests; Janus kinase 2; Male; Megakaryocytes; Mice; Microenvironments; Mutation; Myelofibrosis; Neoplasms; Primary Myelofibrosis - genetics; Primary Myelofibrosis - metabolism; Progenitor cells; Receptors, CXCR4 - metabolism; Stem Cells - metabolism; Tumors; Vascular endothelial growth factor; Weight Loss - drug effects
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.22228

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 Gata1low 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 p27Kip1 activity and is treatable by Aplidin®, a cyclic depsipeptide that activates p27Kip1 in several cancer cells. Aplidin® restored expression of Gata1 and p27Kip1 in Gata1low 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 Gata1low 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 Gata1low progenitor cells remained low. These results indicate that Aplidin® effectively alters the natural history of myelofibrosis in Gata1low mice and suggest this drug as candidate for clinical evaluation in PMF. J. Cell. Physiol. 225: 490–499, 2010. © 2010 Wiley‐Liss, Inc.