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Haematologica. 2019 Mar;104(3):533-545. doi: 10.3324/haematol.2018.188664. Epub 2018 Sep 27.

ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.

Author information

1
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza.
2
Department of Women's and Children's Health, University of Padova.
3
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano.
4
Department of Paediatric Haematology-Oncology and Cell and Gene Therapy, IRCCS Ospedale Pediatrico Bambino Gesù and Sapienza University of Rome.
5
Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza.
6
Medical Statistics Unit, Department of Clinical Medicine and Prevention, University of Milano-Bicocca.
7
School of Medicine and Surgery, University of Milano-Bicocca, Monza.
8
School of Medicine and Surgery, University of Milano-Bicocca.
9
Department of Obstetrics and Gynecology, University of Milano-Bicocca, Monza, Italy.
10
Centro Ricerca Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Fondazione MBBM, Monza giovanna.damico@hsgerardo.org.

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-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.

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