ROCK AS THERAPEUTICAL TARGET FOR MORGANA LOW CML

Background:Atypical chronic myeloid leukemia (aCML) is an haematological neoplasm characterized by a median overall survival of 12.4 months. The standard treatments for aCML patients are chemotherapeutic drugs. However, these treatments result inefficient in inducing remission from the pathology. Recently we demonstrated that the haploinsufficiency of Morgana, an Hsp90 co-chaperone, in vivo is sufficient to induce a lethal and transplantable CML-like myeloid neoplasm characterized by non recurrent cytogenetic abnormalities in the bone marrow. Morgana is able to bind to and inhibit Rho-kinases, which are emerging as key oncogenic players in haematological disorders Aims: Identify fundamental altered pathways in aCML to uncover the biological basis of the disease and find new therapeutical targets. Methods: The bone marrow of morgana heterozygous mice and chronic myeloid leukemia patients has been analyzed extensively by flow cytometry and immunoistochemestry. Murine and human CML bone marrow cells and in vitro cellular models (K562 and THP-1 cells) have been tested for sensitivity to the ROCK inhibitor Fasudil. Results: We demonstrated that diseased morgana heterozygous mice show ROCK hyperactivation in the bone marrow and that inhibition of these kinases results in apoptosis of morganalow bone marrow leukemic cells without affecting normal cells survival. Moreover, in THP-1 cells Morgana downregulation enhances ROCK activity promoting cell proliferation while ROCK inhibition significantly reduces the proliferation of these cells. Interestingly, we found that the Morgana-ROCK pathway is altered in the 16% of Philadelphia-positive CML patients where ROCK hyperactivation, cooperating with BCR-ABL signalling, leads to imatinib resistance. In this context, treatment with a ROCK inhibitor restores the efficacy of imatinib to induce apoptosis. In addition, we found Morgana downregulation and ROCK hyperactivation in the bone marrow of all aCML patients we tested. Summary/Conclusions: Taken together these results point out Morgana as an oncosuppressor and ROCK as potential therapeutical target for Morganalow CML patients.