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Acute Lymphoblastic Leukemia
ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells
Federica Portale,1 Giulia Cricrì,1 Silvia Bresolin,2 Monica Lupi,3
Stefania Gaspari,4.5 Daniela Silvestri,6,7 Barbara Russo,1 Noemi Marino,1 Paolo Ubezio,3 Fabio Pagni,8 Patrizia Vergani,9 Geertruy Te Kronnie,2
Maria Grazia Valsecchi,6 Franco Locatelli,4 Carmelo Rizzari,7 Andrea Biondi,1,7 Erica Dander1* and Giovanna D’Amico1*
Ferrata Storti Foundation
Haematologica 2019 Volume 104(3):533-545
*ED and GD’A contributed equally to this work
1Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza; 2Department of Women’s and Children’s Health, University of Padova; 3Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano; 4Department of Paediatric Haematology-Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù and Sapienza University of Rome; 5Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza; 6Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca; 7School of Medicine and Surgery, University of Milano-Bicocca, Monza; 8School of Medicine and Surgery, University of Milano-Bicocca and 9Department of Obstetrics and Gynecology, University of Milano-Bicocca,
Monza, Italy
ABSTRACT
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-b family mem- ber 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-inflamma- tory 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 promot- ed 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.
Introduction
Acute lymphoblastic leukemia (ALL) is the most frequent childhood malignancy worldwide. B-cell precursor (BCP)-ALL represents about 80% of ALL cases and mainly affects children, with an incidence of 3-4 cases per 100,000 each year.1 Even
Correspondence:
GIOVANNA D’AMICO
giovanna.damico@hsgerardo.org
Received: January 24, 2018. Accepted: September 21, 2018. Pre-published: September 27, 2018.
doi:10.3324/haematol.2018.188664
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/3/533
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haematologica | 2019; 104(3)
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