@article{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_2019, place={Pavia, Italy}, title={ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells}, volume={104}, url={https://haematologica.org/article/view/8811}, DOI={10.3324/haematol.2018.188664}, abstractNote={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<sup>+</sup&gt; 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.}, number={3}, journal={Haematologica}, author={Federica Portale and Giulia Cricrì and Silvia Bresolin and Monica Lupi and Stefania Gaspari and Daniela Silvestri and Barbara Russo and Noemi Marino and Paolo Ubezio and Fabio Pagni and Patrizia Vergani and Geertruy Te Kronnie and Maria Grazia Valsecchi and Franco Locatelli and Carmelo Rizzari and Andrea Biondi and Erica Dander and Giovanna D’Amico}, year={2019}, month={Feb.}, pages={533-545} }