Six6 Is A Tal1-Regulated Transcription Factor In T-All And Associated With Inferior Outcome

T-cell acute lymphoblastic leukemia (T-ALL) is a hematological malignancy driven by abnormal activity of transcription factors. Here we report an aberrant expression of the developmental transcription factorSIX6in the TAL1-subtype of T-ALL. Our results demonstrate that the binding of TAL1 and GATA3 transcription factors into an upstream enhancer element directly regulates SIX6 expression. High expression of SIX6 was associated with inferior event-free survival within three independent patient cohorts. At a functional level, CRISPR-Cas9-mediated knockout of theSIX6gene in TAL1 positive Jurkat cells induced changes in genes associated with the mTOR-, K-RAS-, and TNF alpha-related molecular signatures but did not impair cell proliferation or viability. There was also no acceleration of T-ALL development within a Myc driven zebrafish tumor modelin vivo. Taken together, our results show that SIX6 belongs to the TAL1 regulatory gene network in T-ALL but is alone insufficient to influence the development or maintenance of T-ALL.