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• W2919370328 abstract "•The BM niche can provide proleukemic stimuli to TEL-AML1 preleukemic clones.•Activin A is highly produced by BM stroma cells.•Activin A provides a relative growth advantage to TEL-AML1 preleukemic clones.•Activin A downmodulates CXCL12 production by BM mesenchymal stromal cells.•Activin A, in concert with TGF-β, could contribute to preleukemia-to-leukemia transition. The TEL-AML1 fusion gene, generated by the t(12;21) chromosome translocation, arises in a progenitor/stem cell and could induce clonal expansion of a persistent preleukemic B-cell clone which, on acquisition of secondary alterations, may turn into full-blown leukemia. During infections, deregulated cytokine signaling, including transforming growth factor β (TGF-β), can further accelerate this process by creating a protumoral bone marrow (BM) microenvironment. Here, we show that activin A, a member of the TGF-β family induced under inflammatory conditions, inhibits the proliferation of normal progenitor B cells but not that of preleukemic TEL-AML1–positive clones, thereby providing a selective advantage to the latter. Finally, we find that activin A inhibits BM-derived mesenchymal stromal cell-mediated secretion of CXCL12, a major chemoattractant in the BM compartment, thereby contributing to shape a leukemia-promoting environment. Overall, our findings indicate that activin A, in concert with TGF-β, could play an important role in the creation of a pro-oncogenic BM microenvironment and provide novel mechanistic insights into TEL-AML1-associated leukemogenesis. The TEL-AML1 fusion gene, generated by the t(12;21) chromosome translocation, arises in a progenitor/stem cell and could induce clonal expansion of a persistent preleukemic B-cell clone which, on acquisition of secondary alterations, may turn into full-blown leukemia. During infections, deregulated cytokine signaling, including transforming growth factor β (TGF-β), can further accelerate this process by creating a protumoral bone marrow (BM) microenvironment. Here, we show that activin A, a member of the TGF-β family induced under inflammatory conditions, inhibits the proliferation of normal progenitor B cells but not that of preleukemic TEL-AML1–positive clones, thereby providing a selective advantage to the latter. Finally, we find that activin A inhibits BM-derived mesenchymal stromal cell-mediated secretion of CXCL12, a major chemoattractant in the BM compartment, thereby contributing to shape a leukemia-promoting environment. Overall, our findings indicate that activin A, in concert with TGF-β, could play an important role in the creation of a pro-oncogenic BM microenvironment and provide novel mechanistic insights into TEL-AML1-associated leukemogenesis. The t(12;21) is the most frequent chromosomal lesion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [1Pui CH Relling MV Downing JR Acute lymphoblastic leukemia.N Engl J Med. 2004; 350: 1535-1548Crossref PubMed Scopus (1014) Google Scholar]. The translocation gives rise to the TEL-AML1 fusion gene, which results in the generation of a persistent preleukemic clone [2Wiemels JL Cazzaniga G Daniotti M et al.Prenatal origin of acute lymphoblastic leukaemia in children.Lancet. 1999; 354: 1499-1503Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar]. Because this alteration is insufficient for leukemogenesis, additional secondary postnatal genetic events are necessary for the transition of silent preleukemic cells to overt ALL [3Mullighan CG Goorha S Radtke I et al.Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1365) Google Scholar]. Previous epidemiological and experimental studies have demonstrated the impact of infections and inflammation in the definition of an oncogenic environment able to favor TEL-AML1–expressing clones [4Greaves M Infection, immune responses and the aetiology of childhood leukaemia.Nat Rev Cancer. 2006; 6: 193-203Crossref PubMed Scopus (478) Google Scholar]. Notably, we have previously reported that transforming growth factor β (TGF-β) confers a selective advantage to translocation-bearing clones over healthy cells [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar]. In particular, we found that TEL-AML1–expressing clones are insensitive to the growth-inhibitory effect of TGF-β caused by genetic blockade of SMAD signaling. By this mechanism, TEL-AML1–expressing cells, despite displaying reduced proliferation levels, may acquire a selective advantage over their normal counterparts [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar].Activin A is a TGF-β family member highly produced by mesenchymal stromal cells (MSCs) [6Ichii M Oritani K Yokota T et al.Regulation of human B lymphopoiesis by the transforming growth factor-beta superfamily in a newly established coculture system using human mesenchymal stem cells as a supportive microenvironment.Exp Hematol. 2008; 36: 587-597Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar] and specifically induced by pro-inflammatory stimuli [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar, 8de Kretser DM O'Hehir RE Hardy CL Hedger MP The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair.Mol Cell Endocrinol. 2012; 359: 101-106Crossref PubMed Scopus (116) Google Scholar]. It signals through transmembrane serine/threonine kinase type II receptors (ACVR2A or ACVR2B), which transphosphorylate type I receptors (ALK2, ALK4 or ALK7), initiating both SMAD-dependent and -independent signaling pathways [9Derynck R Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling.Nature. 2003; 425: 577Crossref PubMed Scopus (4199) Google Scholar]. Recent studies on solid cancers have indicated that activin A acts as a key regulator of carcinogenesis by directly modulating cancer cell behavior and creating a tumor-supportive microenvironment [10Loomans HA Andl CD. Intertwining of activin A and TGFβ signaling: Dual roles in cancer progression and cancer cell invasion.Cancers (Basel). 2015; 7: 70-91Crossref Scopus (97) Google Scholar]. In addition, our group has recently demonstrated that activin A exerts a leukemia-promoting role by enhancing the migratory and invasive properties of BCP-ALL cells to the detriment of healthy hematopoiesis within the leukemic niche [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar].To assess a potential role of activin A in preleukemia-to-leukemia transition, we first aimed to determine whether this molecule could favor the persistence of preleukemic clones using an already established inducible TEL-AML1 system derived from murine pro-B Ba/F3 cells [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar]. Furthermore, we sought to determine whether activin A could generate a leukemia-favoring microenvironment by modulating stroma-derived CXCL12, a crucial regulator of normal hematopoietic progenitors.MethodsBa/F3 cultureBa/F3 cells (kindly provided by Dr. Anthony Ford) were cultured as previously described [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar]. Cells induced to express TEL-AML1 (T/A+) and control cells (T/A–) were obtained and cultured as described in the Supplemental Material (online only, available at www.exphem.org).Co-culture experiments of T/A+ and T/A− cellsAfter induction of TEL-AML1, T/A+ cells were co-cultured with T/A–, at a ratio of about 90% to 10%, respectively, in the presence or not of murine MSC (mMSC) monolayers, as described in the Supplemental Material.Activin receptor analyses on Ba/F3 and hMSCsActivin receptors were evaluated as described in the Supplemental Material.Human BM-MSC stimulation and CXCL12 evaluationMSCs were isolated from the bone marrow (BM) of 10 pediatric healthy donors (HDs) as previously described [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar]. Human BM specimens were obtained from healthy BM donors at the Pediatric Department of Fondazione MBBM/San Gerardo Hospital (Monza, Italy; AIEOP-BFM ALL 2009 Protocol). MSCs were cultured and stimulated as described in the Supplemental Material.CXCR4, CXCR7, and CXCL12 stainingCXCR4, CXCR7, and CXCL12 expression levels in hBM-MSCs treated or not with activin A were determined by flow cytometry (Supplemental Material).Statistical analysesDifferences between subgroups were compared with the Mann–Whitney test or Wilcoxon matched-pairs signed rank test in the case of matched values. An analysis of variance (ANOVA) test was used in cases of multiple comparisons.ResultsTo investigate the impact of activin A on the proliferation of TEL-AML1–expressing preleukemic clones, we first evaluated the expression of activin receptors on murine Ba/F3 B-cell precursors, induced to express the fusion gene. Although Ba/F3 cells expressed Alk4 and Acvr2b genes, they were negative for Alk2, Alk7, and Acvr2a mRNA expression (Supplemental Figure E1, online only, available at www.exphem.org). Interestingly, induction of the TEL-AML1 (T/A) fusion gene significantly upregulated Alk4 expression at both the mRNA (Supplemental Figure E1) and protein levels (median MFI T/A– cells: 23.0, range: 6.1–83.2, vs. median MFI T/A+ cells: 124.4, range: 64.6–295.4, P < 0.05) (Figure 1A). In addition, Acvr2b was overexpressed on T/A+ cells (median MFI: 1633, range: 803.2–2288) compared with T/A– control cells (median MFI: 656.3, range: 164–1010, P < 0.05) only at the protein level (Figure 1A).Because we have previously reported that TGF-β selectively inhibits proliferation of T/A– but not T/A+ clones, thereby favoring clonal expansion of the latter [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar], we asked whether activin A would similarly exert a permissive role in T/A+ preleukemic clone persistence. Indeed, although activin A treatment inhibited T/A– Ba/F3 cell proliferation by 43.6% at day +3 of culture, it did not affect T/A+ Ba/F3 cell growth (Supplemental Figure E2, online only, available at www.exphem.org).Next, we sought to determine whether activin A would also favor preleukemic clone persistence under co-culture conditions. To this end, we co-cultured T/A+ and T/A– Ba/F3 cells at a ratio of about 90% to 10%, respectively and measured the percentage of T/A+ cells over a 3-day period. In line with our previous findings [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar], the percentage of T/A+ cells decreased from 90% at day 0 to a median of 36.8% (range: 13.9%–39.6%) at day +3 of co-culture, whereas the median percentage of TGF-β-treated T/A+ clones, similarly co-cultured, decreased to a much lesser extent, with a median value of 51.8% (range: 24.1%–69.1%, P < 0.0001 vs. unstimulated condition) (Supplemental Figure E3, online only, available at www.exphem.org). As expected from our monoculture experiments, activin A also conferred a selective advantage to T/A+ cells, with the median reaching a value of 49.2% after 3 days of co-culture (range: 28.2%–54.4%, P < 0.0001, vs. unstimulated condition) (Supplemental Figure E3). Lastly, combined treatment with activin A and TGF-β did not have an additive effect (Figure 1B and Supplemental Figure E3).Next, to mimic the BM niche, we performed co-culture experiments in which the above-mentioned mixed Ba/F3 population (T/A+ to T/A– cells: 90%–10%) was cultured on a confluent monolayer of murine BM-MSCs in the presence or not of activin A and/or TGF-β (Figure 1B, 7 selected experiments out of 13 shown in Supplemental Figure E3). Also, in this more physiological context, both molecules were able to provide a growth advantage to T/A+ cells (activin A: P < 0.05, TGF-β: P < 0.001, vs. unstimulated condition). On the other hand, the single addition of the MSC monolayer to the mixed culture did not result in improved survival of T/A+ cells (Figure 1B), suggesting that activin A and TGF-β are required for this process.To study whether activin A could promote a pro-leukemic BM microenvironment, we evaluated activin receptors on healthy BM-derived MSCs. As illustrated in Figure 2A and B, we could readily detect ALK2, ALK7, and ACVR2A protein expression in MSCs, indicating that these cells are indeed potential targets of activin A.Figure 2Activin receptor expression on human BM-MSCs. (A) Western blot analysis of hBM-MSC protein extracts from three different healthy donors (HDs) using an antibody anti-human ALK2 protein (57 kDa) or anti-human β-actin (43 kDa) as loading control. (B) On the left are flow cytometry histograms for the identification of cell surface ALK4, ALK7, ACVR2A, and ACVR2B expression of one of six MSC specimens tested (positive: cells stained with fluorescent dye-conjugated antibody; negative: cells stained with isotype-matched control in the case of ALK4, ALK7, and ACVR2A or stained with only secondary antibody in the case of ACVR2B). On the right are the mean fluorescence intensity (MFI) values for ALK4, ALK7, ACVR2A, and ACVR2B expression in six different HD-MSCs (horizontal lines represent median values).View Large Image Figure ViewerDownload Hi-res image Download (PPT)As leukemic BM has recently been reported to exhibit reduced expression of CXCL12, a well-known regulator of normal hematopoiesis [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar, 11van den Berk LC van der Veer A Willemse ME et al.Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia.Br J Haematol. 2014; 166: 240-249Crossref PubMed Scopus (53) Google Scholar], we next asked whether activin A, alone or in combination with TGF-β, would impair MSC-mediated secretion of CXCL12. Remarkably, MSC treatment with either cytokine led to a similar and significant drop in CXCL12 production (activin A: 29.6% median reduction, range: –2.6% to 47.3%, P < 0.01, vs. unstimulated condition; TGF-β: 29.8% median reduction, range: 6.0%–69.9%, P < 0.01, vs. unstimulated condition) (Figure 3A). The decrease in MSC-derived CXCL12 after 24 and 48 h of stimulation with activin A was further demonstrated at the mRNA level (Supplemental Figure E4, online only, available at www.exphem.org). Furthermore, MSC stimulation with a cocktail of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor α significantly decreased CXCL12 production by MSCs (Supplemental Figure E5, online only, available at www.exphem.org).Figure 3Activin A impairs CXCL12 release by human BM-MSCs. (A) CXCL12 secretion by HD-derived BM-MSCs (n = 8 for each condition) was assessed by enzyme-linked immunosorbent assay (ELISA) after 72 h of stimulation with activin A (100 ng/mL) ± TGF-β (10 ng/mL). Each boxplot illustrates the median and the mean (+) and extends from the lowest to the highest value. *P < 0.05, **P < 0.01: analysis of variance test. (B) CXCR4 and CXCR7 levels were evaluated by flow cytometry on the membranes of six different BM-MSC lines stimulated or not with activin A (100 ng/mL). The graphs illustrate the mean fluorescence intensity (MFI) values for CXCR4 and CXCR7 measured at three different time points (24, 48, or 72 h after stimulation). Each boxplot depicts the median and the mean (+) and extends from the lowest to the highest value. (C) The amount of membrane-bound CXCL12 was evaluated by flow cytometry on six different BM-MSC lines stimulated or not with activin A (100 ng/mL). Each boxplot depicts the median and the mean (+) and extends from the lowest to the highest value.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Trying to dissect the contribution of membrane-bound CXCL12 to the observed effect, we demonstrated that activin A stimulation did not alter the expression of CXCR4 and CXCR7 on MSC membrane (Figure 3B). We next evaluated the fraction of CXCL12 that can be sequestered and presented on the cell membrane by glycosaminoglycans (GAGs) [12Murphy JW Cho Y Sachpatzidis A Fan C Hodsdon ME Lolis E Structural and functional basis of CXCL12 (stromal cell-derived factor-1 alpha) binding to heparin.J Biol Chem. 2007; 282: 10018-10027Crossref PubMed Scopus (142) Google Scholar], independently of its receptors CXCR4 and CXCR7. By using an anti-CXCL12 antibody, we found that activin A stimulation for 24 or 48 h did not alter the amount of membrane-bound CXCL12. In contrast, after 72 h of activin A stimulation, we observed a slight upregulation of membrane-bound CXCL12, albeit not statistically significant when compared with unstimulated control cells (Figure 3C).DiscussionThe onset of ALL has been linked to the cooperation of environmental exposures with genetic lesions. It has been shown that the t(12;21)-derived TEL-AML1 fusion protein is a frequent initiating event in childhood ALL able to induce a preleukemic phenotype. Inflammatory conditions, such as infections, may provide a promoting background for overt leukemia [4Greaves M Infection, immune responses and the aetiology of childhood leukaemia.Nat Rev Cancer. 2006; 6: 193-203Crossref PubMed Scopus (478) Google Scholar]. TGF-β has been identified as a leukemia-favoring factor, mediating a marked advantage to TEL-AML1–expressing clones [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar].Activin A is a member of the TGF-β family, whose expression is increased in infections and inflammatory diseases [13Sozzani S Musso T. The yin and yang of activin A.Blood. 2011; 117: 5013-5015Crossref PubMed Scopus (22) Google Scholar]. Evidence of its pro-tumoral role within the BCP-ALL BM niche [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar] prompted us to investigate whether activin A favors the preleukemia-to-leukemia transition. Here, we demonstrated that activin A, in combination with TGF-β, can exert dual leukemia-promoting activity by directly acting on both preleukemic cells and the surrounding BM stroma.In co-culture experiments we found that activin A is able to sustain TEL-AML1–expressing clones to the detriment of their normal counterparts. Indeed, while T/A+ cell count was stable on activin A, TGF-β [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar], or activin A + TGF-β stimulation, the growth of T/A– Ba/F3 cells was significantly impaired. It is conceivable that activin A, similarly to TGF-β, could exert a SMAD-mediated anti-proliferative effect [14Carcamo J Weis FM Ventura F et al.Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.Mol Cell Biol. 1994; 14: 3810-3821Crossref PubMed Google Scholar] on normal B progenitors, as already observed in other cell types [15Burdette JE Jeruss JS Kurley SJ Lee EJ Woodruff TK Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells.Cancer Res. 2005; 65: 7968-7975Crossref PubMed Scopus (108) Google Scholar, 16Hashimoto O Yamato K Koseki T et al.The role of activin type I receptors in activin A-induced growth arrest and apoptosis in mouse B-cell hybridoma cells.Cell Signalling. 1998; 10: 743-749Crossref PubMed Scopus (27) Google Scholar]. On the other hand, as previously demonstrated for TGF-β [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar], TEL-AML1–expressing clones are insensitive to activin A, likely because of constitutive inhibition of SMAD signaling, which confers on them a growth advantage over their non-expressing counterparts. The blockade of SMAD signaling in TEL-AML1–expressing cells does not seem to preclude these cells from being responsive to activin A stimulation through other non-SMAD-mediated pathways, as suggested by enhanced expression levels of the Alk4 and Acvr2b activin receptors observed on these cells. In this regard, ALK4 overexpression has been previously associated with cancer stem cell persistence in different tumors [17Lonardo E Hermann PC Mueller MT et al.Nodal/activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy.Cell Stem Cell. 2011; 9: 433-446Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, 18Ohno Y Shingyoku S Miyake S et al.Differential regulation of the sphere formation and maintenance of cancer-initiating cells of malignant mesothelioma via CD44 and ALK4 signaling pathways.Oncogene. 2018; 37: 6357-6367Crossref PubMed Scopus (14) Google Scholar].We recently reported that BM-MSCs can produce high activin A levels under inflammatory conditions [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar]. In line with its ability to promote tumors by editing the surrounding stroma in solid cancers [10Loomans HA Andl CD. Intertwining of activin A and TGFβ signaling: Dual roles in cancer progression and cancer cell invasion.Cancers (Basel). 2015; 7: 70-91Crossref Scopus (97) Google Scholar], here we report that activin A can skew MSCs to a leukemia-favoring phenotype in an autocrine fashion. Specifically, we show that MSCs express type I and II receptors, required for activin A signaling, and that activin A/TGF-β can significantly impair the release of CXCL12 by MSCs, possibly through a SMAD-mediated pathway, as previously demonstrated [19Gillette JM Larochelle A Dunbar CE Lippincott-Schwartz J Intercellular transfer to signaling endosomes regulates an ex vivo bone marrow niche.Nat Cell Biol. 2009; 11: 303-311Crossref PubMed Scopus (82) Google Scholar]. In accordance, our data indicate that the reduction of CXCL12 secretion by activing A-stimulated MSCs can be, at least in part, explained by a decrease in its mRNA levels, thereby ruling out a contribution of CXCL12 sequestration on MSC membrane by its cognate receptors or GAGs. In addition, the stimulation of MSCs with pro-inflammatory cytokines, typically overexpressed in the BCP-ALL BM niche [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar], results in a significant decrease in CXCL12 expression. Intriguingly, reduced expression of CXCL12 appears to be a common feature of the BCP-ALL BM niche, supporting the hypothesis that this decrease might be responsible for leukemogenesis at the expense of normal hematopoiesis [7Portale F Cricri G Bresolin S et al.ActivinA: A new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells.Haematologica. 2019; 104: 533-545Crossref PubMed Scopus (13) Google Scholar, 11van den Berk LC van der Veer A Willemse ME et al.Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia.Br J Haematol. 2014; 166: 240-249Crossref PubMed Scopus (53) Google Scholar, 20Balandrán JC Purizaca J Enciso J et al.Pro-inflammatory-related loss of CXCL12 niche promotes acute lymphoblastic leukemic progression at the expense of normal lymphopoiesis.Front Immunol. 2016; 7: 666PubMed Google Scholar]. In addition, De Rooij et al. [21de Rooij B Polak R van den Berk LCJ Stalpers F Pieters R den Boer ML Acute lymphoblastic leukemia cells create a leukemic niche without affecting the CXCR4/CXCL12 axis.Haematologica. 2017; 102: e389-e393Crossref PubMed Scopus (18) Google Scholar] reported that B-ALL cells are able to alter the BM microenvironment, creating a self-reinforcing niche independent of the CXCR4/CXCL12 axis. Accordingly, the reduction of CXCL12 within the preleukemic BM niche could also be a relevant step in the transition to overt leukemia. In addition to its well-known role as a supporting factor for hematopoietic stem cell quiescence and retention into the BM, recent works have indicated that CXCL12 can mediate protection from oxidative stress and myelotoxic injury [22Sugiyama T Kohara H Noda M Nagasawa T Maintenance of the hematopoietic stem cell pool by CXCL12–CXCR4 chemokine signaling in bone marrow stromal cell niches.Immunity. 2006; 25: 977-988Abstract Full Text Full Text PDF PubMed Scopus (1656) Google Scholar, 23Zhang Y Dépond M He L et al.CXCR4/CXCL12 axis counteracts hematopoietic stem cell exhaustion through selective protection against oxidative stress.Sci Rep. 2016; 6: 37827Crossref PubMed Scopus (58) Google Scholar]. This scenario could increase the susceptibility of preleukemic progenitors to the acquisition of new genetic aberrations leading to disease onset.Overall, we propose that activin A, in concert with TGF-β, could play an important role in the creation of a pro-oncogenic BM microenvironment by directly favoring preleukemic clone expansion and genetic instability through regulation of the CXCL12/CXCR4 axis. Even though molecular targeting of TGF-β and activin A is still far from clinical application, our study paves the way for the identification of new therapies to avoid the transition of preleukemic clones to primary leukemia or its relapse. The t(12;21) is the most frequent chromosomal lesion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) [1Pui CH Relling MV Downing JR Acute lymphoblastic leukemia.N Engl J Med. 2004; 350: 1535-1548Crossref PubMed Scopus (1014) Google Scholar]. The translocation gives rise to the TEL-AML1 fusion gene, which results in the generation of a persistent preleukemic clone [2Wiemels JL Cazzaniga G Daniotti M et al.Prenatal origin of acute lymphoblastic leukaemia in children.Lancet. 1999; 354: 1499-1503Abstract Full Text Full Text PDF PubMed Scopus (518) Google Scholar]. Because this alteration is insufficient for leukemogenesis, additional secondary postnatal genetic events are necessary for the transition of silent preleukemic cells to overt ALL [3Mullighan CG Goorha S Radtke I et al.Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1365) Google Scholar]. Previous epidemiological and experimental studies have demonstrated the impact of infections and inflammation in the definition of an oncogenic environment able to favor TEL-AML1–expressing clones [4Greaves M Infection, immune responses and the aetiology of childhood leukaemia.Nat Rev Cancer. 2006; 6: 193-203Crossref PubMed Scopus (478) Google Scholar]. Notably, we have previously reported that transforming growth factor β (TGF-β) confers a selective advantage to translocation-bearing clones over healthy cells [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar]. In particular, we found that TEL-AML1–expressing clones are insensitive to the growth-inhibitory effect of TGF-β caused by genetic blockade of SMAD signaling. By this mechanism, TEL-AML1–expressing cells, despite displaying reduced proliferation levels, may acquire a selective advantage over their normal counterparts [5Ford AM Palmi C Bueno C et al.The TEL-AML1 leukemia fusion gene dysregulates the TGF-beta pathway in early B lineage progenitor cells.J Clin Invest. 2009; 119: 826-836PubMed Google Scholar]. Activin A is a TGF-β family member highly produced by mesenchyma" @default.
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• W2919370328 date "2019-05-01" @default.
• W2919370328 modified "2023-10-07" @default.
• W2919370328 title "Activin A contributes to the definition of a pro-oncogenic bone marrow microenvironment in t(12;21) preleukemia" @default.
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• W2919370328 doi "https://doi.org/10.1016/j.exphem.2019.02.006" @default.
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