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

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.

Activin A: an emerging target for improving cancer treatment?

“…In liver metastasis, for instance, Activin A produced by the target organ was reported to promote metastasis formation [56]. In the bone marrow niche, activin A production by stromal cells was induced by B-cell precursor-acute lymphoblastic leukemic cells and provided a migratory advantage for leukemic cells over healthy hematopoiesis [57]. Overall, the great majority of studies conclude that activin A has a promigratory and prometastatic function and its inhibition could be used to prevent or reduce metastatic spreading.…”

Characterizing the Motility of Chemotherapeutics-Treated Acute Lymphoblastic Leukemia Cells by Time-Lapse Imaging

“…ActivinA, in turn, caused enhanced cell motility, migration toward CXCL12, and the invasion of B-cell precursor (BCP)-ALL cells as determined by time-lapse microscopy. Furthermore, this in vitro finding was verified by the enhanced in vivo engraftment of BCP-ALL cells to BM and extramedullary sites (peripheral blood, spleen, liver, meninges, and brain) in a xenograft mouse model [ 16 ]. Recent developments in imaging technologies have provided powerful new tools to visualize, image, track, and analyze HSCs and their interactions with the BM niche by labeling with fluorescent dyes such as Qdot 655 [ 17 ].…”

“…The interaction between mesenchymal stromal cells (MSCs) and leukemia cells has been of much interest. Leukemia cells have been described to remodulate the BM microenvironment via stimulating MSCs to release more ActivinA, a pleiotropic cytokine that belongs to the TGF-β superfamily [ 16 ]. ActivinA, in turn, caused enhanced cell motility, migration toward CXCL12, and the invasion of B-cell precursor (BCP)-ALL cells as determined by time-lapse microscopy.…”

The Bone Marrow Niche in B-Cell Acute Lymphoblastic Leukemia: The Role of Microenvironment from Pre-Leukemia to Overt Leukemia

“…As already mentioned, CXCL12, secreted by BM-MSCs, plays an essential role in maintaining the quiescent BM hematopoietic stem cell pool. Independent studies on BM plasma samples of pediatric B-ALL patients at disease diagnosis have demonstrated a dramatic decrease in this chemokine [ 61 , 62 , 63 ]. Alongside, ALL-MSCs have been shown to secrete significantly lower CXCL12 compared to MSCs isolated from healthy donors (HD-MSCs) [ 64 ].…”