Centro Ricerca Tettamanti, Pediatric Department, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy.
Centro Ricerca Tettamanti, Pediatric Department, University of Milano-Bicocca, Fondazione MBBM, Monza, Italy; Clinica Pediatrica Ospedale S. Gerardo, Fondazione MBBM, University of Milano-Bicocca, Monza, Italy.
Exp Hematol. 2019 May;73:7-12.e4. doi: 10.1016/j.exphem.2019.02.006. Epub 2019 Feb 28.
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.
TEL-AML1 融合基因由 t(12;21)染色体易位产生，源于祖细胞/干细胞，并可能诱导持续存在的白血病前 B 细胞克隆的克隆扩增，这些克隆在获得继发性改变后，可能会发展为完全成熟的白血病。在感染过程中，包括转化生长因子-β（TGF-β）在内的失调细胞因子信号可以通过创建促肿瘤性骨髓（BM）微环境进一步加速这一过程。在这里，我们表明，激活素 A，一种在炎症条件下诱导产生的 TGF-β 家族成员，抑制正常祖细胞 B 细胞的增殖，但不抑制白血病前 TEL-AML1 阳性克隆的增殖，从而为后者提供选择性优势。最后，我们发现激活素 A 抑制 BM 来源的间充质基质细胞介导的 CXCL12 的分泌，CXCL12 是 BM 隔室中的主要趋化因子，从而有助于形成促进白血病的环境。总的来说，我们的研究结果表明，激活素 A 与 TGF-β 一起，可能在创建促癌性 BM 微环境中发挥重要作用，并为 TEL-AML1 相关白血病发生提供新的机制见解。
