Dottorato in Medicina Molecolare

The double face of Morgana in tumorigenesis.

Brancaccio M, Rocca S, Seclì L, Busso E, Fusella F.

Oncotarget. 2015 Dec 15;6(40):42603-12. doi: 10.18632/oncotarget.6058. Review.

PMID: 26460959

 

Morgana acts as an oncosuppressor in chronic myeloid leukemia.

Di Savino A*, Panuzzo C*, Rocca S*, Familiari U, Piazza R, Crivellaro S, Carrà G, Ferretti R, Fusella F, Giugliano E, Camporeale A, Franco I, Miniscalco B, Cutrin JC, Turco E, Silengo L, Hirsch E, Rege-Cambrin G, Gambacorti-Passerini C, Pandolfi PP, Papotti M, Saglio G, Tarone G, Morotti A,Brancaccio M.

Blood. 2015 Apr 2;125(14):2245-53. doi: 10.1182/blood-2014-05-575001. Epub 2015 Feb 12.

PMID: 25678499

* This authors contributed equally to this work

 

Morgana acts as a proto-oncogene through inhibition of a ROCK-PTEN pathway.

Fusella F, Ferretti R, Recupero D, Rocca S, Di Savino A, Tornillo G, Silengo L, Turco E, Cabodi S, Provero P, Pandolfi PP, Sapino A, Tarone G, Brancaccio M.

J Pathol. 2014 Oct;234(2):152-63. doi: 10.1002/path.4341. Epub 2014 Aug 6.

PMID: 24615293

 

Morgana acts as an oncosuppressor in chronic myeloid leukemia

 S. Rocca ,  A. Di Savino , C. Panuzzo , U. Familiari , I. Franco , E. Turco , E. Hirsch , P.P. Pandolfi , G. Saglio , G. Tarone , A. Morotti  and M. Brancaccio

Morgana is an ubiquitously expressed protein able to protect cells from stress by acting as a co-chaperone of Hsp90. Other than Hsp90, Morgana is able to interact with ROCK kinases and inhibit their kinase activity. Morgana underexpression results in ROCKII hyperactivation that is responsible for centrosome amplification. Inturn, centrosome abnormalities lead to genomic instability that is an important feature of cancer cells. Morgana heterozygous mice spontaneously develop a fatal myeloproliferative disease characterized by ROCK hyperactivation, centrosome amplification and cytogenetic abnormalities in the bone marrow. This disorder resembles human atypical chronic myeloid leukemia (aCML), a rare neoplasm characterized by non-recurrent cytogenetic abnormalities, whose molecular basis is poorly understood. We found that Morgana is underexpressed in the bone marrow of patients affected by aCML and in a portion of patients affected by Philadelphia-positive chronic myeloid leukemia (Ph+ CML). Moreover we noticed that Morgana underexpression predicts a worse response to Imatinib, the Ph+ CML standard treatment.

Notably, in the bone marrow of patients in which Morgana is underexpressed, treatment with ROCK inhibitor can restore the efficacy of Imatinib to induce apoptosis, overcoming suboptimal responses. Taken together all this data identify Morgana for the first time as an oncosuppressor in chronic myeloid leukemia.

 

ROCK AS THERAPEUTICAL TARGET FOR MORGANA ^LOW CML

Stefania Rocca ,  A. Di Savino , C. Panuzzo , U. Familiari , I. Franco , E. Turco , E. Hirsch , P.P. Pandolfi , G. Saglio , G. Tarone , A. Morotti , M. Brancaccio

 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/Conclusion: Taken together these results point out Morgana as an oncosuppressor and ROCK as potential therapeutical target for Morganalow CML patients.

 

Keywords: Chronic myeloid leukemia, Drug sensitivity, Mouse model

• HSP90 MEETING 2014, 15-19 OTTOBRE 2014, SEEON ABBEY, GERMANIA

• FRONTIERS IN REGENERATIVE MEDICINE, 18-20 FEBBRAIO 2015, TORINO, ITALIA

• SIBBM 2015, 1-3 LUGLIO 2015, TORINO, ITALIA

• ABCD 2015, 17-19 SETTEMBRE 2015, BOLOGNA, ITALIA

• National PhD Meeting ABCD 2016, 7-9 APRILE 2016, SALERNO, ITALIA

• 21^st  Congress of the European Haematology Association, 9-12 GIUGNO 2016, COPENAGHEN, DANIMARCA

 

May 24^th 2016 Turin, “Giornata di studio Guido Tarone”. Organized by Dottorato in Scienze Biomediche e Oncologia and Dottorato in Medicina Molecolare in collaboration with Molecular Biotechnology Center and Turin University.

 

September 2015 Turin University. D-Day

January 2015 “The biology of shape: from Aristotle to stem cells”. Prof. Stefano Piccolo. Scuola di Dottorato in Scienza della Vita e della Salute, corso Medicina Molecolare.