TEL-AML1 Dysregulates the TGFβ Pathway: A Basis for Pre-Leukaemic Stem Cell Selection.

TEL-AML1 fusion is the most frequent, defined genetic abnormality in paediatric cancer and is usually an early or initiating and pre-natal event in childhood acute lymphoblastic leukaemia (ALL). Transformation results in the generation of a persistent pre-leukaemic clone, which converts to frank ALL post-natally (at 1-15years) following the acquisition of secondary genetic alterations. The mechanism by which the transcriptional dysregulation imposed by TEL-AML1 impacts on the pre-leukaemic phenotype and disease natural history is unknown. Using regulated expression of TEL-AML1, we show that, in murine progenitor cells, this protein blocks the TGFβ response pathway including the critical regulator of cell cycle inhibition, p27. This inhibition facilitates the selective expansion of otherwise more slowly expanding TEL-AML1 progenitor cells. The mechanism of action of TEL-AML1 appears to operate downstream of SMAD2/3 phosphorylation (by TGFβ signalling) and involves binding of a transcriptional repressor complex to TGFβ target genes. In transgenic Eμ TEL-AML1 mice, we show that early pro-B cells (but not pre-B cells) are selectively expanded and appear less sensitive to the inhibitory effects of TGFβ than equivalent wild-type cells. Finally, we show that expression of TEL-AML1 in human cord blood progenitor cells leads to the expansion of a candidate pre-leukaemic stem cell population with an early B lineage phenotype (CD34+/CD38-/CD19+) that has a selective growth advantage in the presence of TGFβ.