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 factor SIX6 in the TAL1-subtype of T-ALL. Our results demonstrate that the binding of TAL1 and GATA...

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Bibliographic Details
Published in:Leukemia & lymphoma 2020, Vol.61 (13), p.3089-3100
Main Authors: Laukkanen, Saara, Oksa, Laura, Nikkilä, Atte, Lahnalampi, Mari, Parikka, Mataleena, Seki, Masafumi, Takita, Junko, Degerman, Sofie, de Bock, Charles E., Heinäniemi, Merja, Lohi, Olli
Format: Article
Language:English
Subjects:
aberrant gene expression
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Cell Line, Tumor
event-free survival
Homeodomain Proteins
Humans
Medicin och hälsovetenskap
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Proto-Oncogene Proteins - genetics
SIX6
T-cell acute lymphoblastic leukemia
T-Cell Acute Lymphocytic Leukemia Protein 1
TAL1
Trans-Activators
Zebrafish - genetics
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Summary: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.
ISSN:1042-8194
1029-2403
1029-2403
DOI:10.1080/10428194.2020.1804560