Chromosome translocation to generate the TEL-AML1 (also known as ETV6-RUNX1) chimeric fusion gene is a frequent and early or initiating event in childhood acute lymphoblastic leukemia (ALL). Our starting hypothesis was that the TEL-AML1 protein generates and maintains preleukemic clones and that conversion to overt disease requires secondary genetic changes, possibly in the context of abnormal immune responses. Here, we show that a murine B cell progenitor cell line expressing inducible TEL-AML1 proliferates at a slower rate than parent cells but is more resistant to further inhibition of proliferation by TGF-β. This facilitates the competitive expansion of TEL-AML1–expressing cells in the presence of TGF-β. Further analysis indicated that TEL-AML1 binds to a principal TGF-β signaling target, Smad3, and compromises its ability to activate target promoters. In mice expressing a TEL-AML1 transgene, early, pre-pro-B cells were increased in number and also showed reduced sensitivity to TGF-β–mediated inhibition of proliferation. Moreover, expression of TEL-AML1 in human cord blood progenitor cells led to the expansion of a candidate preleukemic stem cell population that had an early B lineage phenotype (CD34+CD38–CD19+) and a marked growth advantage in the presence of TGF-β. Collectively, these data suggest a plausible mechanism by which dysregulated immune responses to infection might promote the malignant evolution of TEL-AML1–expressing preleukemic clones.
Anthony M. Ford, Chiara Palmi, Clara Bueno, Dengli Hong, Penny Cardus, Deborah Knight, Giovanni Cazzaniga, Tariq Enver, Mel Greaves
Title and authors | Publication | Year |
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The distinct effects of P18 overexpression on different stages of hematopoiesis involve TGF-β and NF-κB signaling
Yi D, Zhu L, Liu Y, Zeng J, Chang J, Sun W, Teng J, Zhang Y, Dong Y, Pan X, Chen Y, Zhou Y, Lai M, Zhou Q, Liu J, Chen B, Ma F |
Scientific Reports | 2021 |
Can we prevent childhood Leukaemia?
Greaves M, Cazzaniga V, Ford A |
Leukemia | 2021 |
Genome-wide interference of ZNF423 with B-lineage transcriptional circuitries in acute lymphoblastic leukemia.
Iglesias P, Puller AC, Seoane M, Spohn M, Raasch S, Klokow M, Müller J, Burkhardt L, Indenbirken D, Horstmann MA |
Blood Advances | 2021 |