ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells
Federica Portale,
Giulia Cricrì,
Silvia Bresolin,
Monica Lupi,
Stefania Gaspari,
Daniela Silvestri,
Barbara Russo,
Noemi Marino,
Paolo Ubezio,
Fabio Pagni,
Patrizia Vergani,
Geertruy Te Kronnie,
Maria Grazia Valsecchi,
Franco Locatelli,
Carmelo Rizzari,
Andrea Biondi,
Erica Dander,
Giovanna D’Amico
Affiliations
Federica Portale
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
Giulia Cricrì
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
Silvia Bresolin
Department of Women’s and Children’s Health, University of Padova
Monica Lupi
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano
Stefania Gaspari
Department of Paediatric Haematology-Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù and Sapienza University of Rome;Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza
Daniela Silvestri
Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca;School of Medicine and Surgery, University of Milano-Bicocca, Monza
Barbara Russo
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
Noemi Marino
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
Paolo Ubezio
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano
Fabio Pagni
School of Medicine and Surgery, University of Milano-Bicocca
Patrizia Vergani
Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy
Geertruy Te Kronnie
Department of Women’s and Children’s Health, University of Padova
Maria Grazia Valsecchi
Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca
Franco Locatelli
Department of Paediatric Haematology-Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù and Sapienza University of Rome
Carmelo Rizzari
School of Medicine and Surgery, University of Milano-Bicocca, Monza
Andrea Biondi
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza;School of Medicine and Surgery, University of Milano-Bicocca, Monza
Erica Dander
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
Giovanna D’Amico
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza
B-cell precursor-acute lymphoblastic leukemia modulates the bone marrow (BM) niche to become leukemia-supporting and chemo-protective by reprogramming the stromal microenvironment. New therapies targeting the interplay between leukemia and stroma can help improve disease outcome. We identified ActivinA, a TGF-β family member with a well-described role in promoting several solid malignancies, as a factor favoring leukemia that could represent a new potential target for therapy. ActivinA resulted over-expressed in the leukemic BM and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, MSCs isolated from BM of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterparts. The pro-inflammatory leukemic BM microenvironment synergized with leukemic cells to induce stromal-derived ActivinA. Gene expression analysis of ActivinA-treated leukemic cells showed that this protein was able to significantly influence motility-associated pathways. Interestingly, ActivinA promoted random motility and CXCL12-driven migration of leukemic cells, even at suboptimal chemokine concentrations, characterizing the leukemic niche. Conversely, ActivinA severely impaired CXCL12-induced migration of healthy CD34+ cells. This opposite effect can be explained by the ability of ActivinA to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through a higher rate of actin polymerization. Moreover, by stimulating the invasiveness of the leukemic cells, ActivinA was found to be a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance BM engraftment and the metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA was seen to be a key factor in conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche.
