B-cell precursor-Acute Lymphoblastic Leukemia modulates the bone marrow niche to become leukemia-supporting and chemoprotective by reprogramming the stromal microenvironment. New therapies targeting the leukemia/stroma interplay can be instrumental to improve disease outcome. We identified ActivinA, a TGF-β family member, with a well-described promoting role in several solid malignancies, as a new potentially targetable leukemia-favoring factor. ActivinA resulted overexpressed in the leukemic bone marrow and its production was strongly induced in mesenchymal stromal cells after culture with leukemic cells. Moreover, mesenchymal stromal cells isolated from bone marrow of leukemic patients showed an intrinsic ability to secrete higher amounts of ActivinA compared to their normal counterpart. The pro-inflammatory leukemic bone marrow 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 ActivinA ability to increase intracellular calcium only in leukemic cells, boosting cytoskeleton dynamics through higher rate of actin polymerization. Moreover, by stimulating leukemic cell invasiveness, ActivinA resulted a leukemia-promoting factor. Importantly, the ability of ActivinA to enhance the bone marrow engraftment and metastatic potential of leukemic cells was confirmed in a xenograft mouse model of the disease. Overall, ActivinA resulted a key factor conferring a migratory advantage to leukemic cells over healthy hematopoiesis within the leukemic niche.