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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalHaematologica
DOIs
Publication statusE-pub ahead of print - Sep 27 2018

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B-Lymphoid Precursor Cells
Leukemia
Bone Marrow
Aptitude
Mesenchymal Stromal Cells
Hematopoiesis
Cytoskeleton
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Chemokines
Heterografts
Polymerization
Cell Movement
Actins
Cell Culture Techniques
Calcium
Gene Expression

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ActivinA : a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells. / Portale, Federica; Cricrì, Giulia; Bresolin, Silvia; Lupi, Monica; Gaspari, Stefania; Silvestri, Daniela; Russo, Barbara; Marino, Noemi; Ubezio, Paolo; Pagni, Fabio; Vergani, Patrizia; Te Kronnie, Geertruy; Valsecchi, Maria Grazia; Locatelli, Franco; Rizzari, Carmelo; Biondi, Andrea; Dander, Erica; D'Amico, Giovanna.

In: Haematologica, 27.09.2018.

Research output: Contribution to journalArticle

Portale, F, Cricrì, G, Bresolin, S, Lupi, M, Gaspari, S, Silvestri, D, Russo, B, Marino, N, Ubezio, P, Pagni, F, Vergani, P, Te Kronnie, G, Valsecchi, MG, Locatelli, F, Rizzari, C, Biondi, A, Dander, E & D'Amico, G 2018, 'ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells', Haematologica. https://doi.org/10.3324/haematol.2018.188664
Portale, Federica ; Cricrì, Giulia ; Bresolin, Silvia ; Lupi, Monica ; Gaspari, Stefania ; Silvestri, Daniela ; Russo, Barbara ; Marino, Noemi ; Ubezio, Paolo ; Pagni, Fabio ; Vergani, Patrizia ; Te Kronnie, Geertruy ; Valsecchi, Maria Grazia ; Locatelli, Franco ; Rizzari, Carmelo ; Biondi, Andrea ; Dander, Erica ; D'Amico, Giovanna. / ActivinA : a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells. In: Haematologica. 2018.
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abstract = "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.",
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T2 - a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells

AU - Portale, Federica

AU - Cricrì, Giulia

AU - Bresolin, Silvia

AU - Lupi, Monica

AU - Gaspari, Stefania

AU - Silvestri, Daniela

AU - Russo, Barbara

AU - Marino, Noemi

AU - Ubezio, Paolo

AU - Pagni, Fabio

AU - Vergani, Patrizia

AU - Te Kronnie, Geertruy

AU - Valsecchi, Maria Grazia

AU - Locatelli, Franco

AU - Rizzari, Carmelo

AU - Biondi, Andrea

AU - Dander, Erica

AU - D'Amico, Giovanna

N1 - Copyright © 2018, Ferrata Storti Foundation.

PY - 2018/9/27

Y1 - 2018/9/27

N2 - 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.

AB - 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.

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DO - 10.3324/haematol.2018.188664

M3 - Article

C2 - 30262563

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -