SIX6 is a TAL1-regulated transcription factor in T-ALL and associated with inferior outcome

Abstract

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 factor SIX6 in 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 the SIX6 gene in TAL1 positive Jurkat cells induced changes in genes associated with the mTOR-, K-RAS-, and TNFα-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 model in 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.

Keywords:

• T-cell acute lymphoblastic leukemia
• SIX6
• TAL1
• event-free survival
• aberrant gene expression

Acknowledgments

The authors wish to thank Jorma Kulmala, Eini Eskola, Noora Hyvärinen and Jalmari Kettunen for assistance in laboratory work and bioinformatic analyses.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the Academy of Finland (O.L. and M.H. [321553], O.L. [310106], M.P. [316324 and 322010]), Syöpäsäätiö (O.L., M.H), Jane ja Aatos Erkon Säätiö (O.L., M.H., M.P.), Sigrid Juselius Foundation (O.L., M.H., M.P.), Finnish Hematology Association (S.L.), Tampereen Tuberkuloosisäätiö (M.P.), The Swedish Childhood Cancer Fund (S.D.) and the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (O.L. [9V033 and 9X027]). Tampere University Zebrafish Core Facility was supported by funding from Biocenter Finland.