Conclusion
Overall, our data contributes to the understanding of the role of TGF-β signaling in acute myeloid leukemia with KMT2A::AFF1 by showing that SMAD1 loss can influence the growth dynamics and contribute to the pathogenic expression of disease driving factors.
Results
Here we report the KMT2A::AFF1 and KMT2A::MLLT3 fusion gene-dependent downregulation of SMAD1, a TGF-β signaling axis transcription factor. SMAD1 expression is lost in the majority of AML patient samples and cell lines containing the two fusion genes KMT2A::AFF1 and KMT2A::MLLT3 compared to non-rearranged controls. Loss of SMAD1 expression is inducible by introducing the respective two KMT2A fusion genes into hematopoietic stem and progenitor cells. The loss of SMAD1 correlated with a markedly reduced amount of H3K4me3 levels at the SMAD1 promoter in tested cells with KMT2A::AFF1 and KMT2A::MLLT3. The expression of SMAD1 in cells with KMT2A::AFF1 fusion genes impacted the growth of cells in vitro and influenced engraftment of the KMT2A::AFF1 cell line MV4-11 in vivo. In MV4-11 cells SMAD1 expression caused a downregulation of HOXA9 and MEIS1, which was reinforced by TGF-β stimulation. Moreover, in MV4-11 cells SMAD1 presence sensitized cells for TGF-β mediated G1-arrest.