FAT1 expression in T-cell acute lymphoblastic leukemia (T-ALL) modulates proliferation and WNT signaling
FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The FAT1 gene is mutated in 12–16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases co...
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Published in | Scientific reports Vol. 13; no. 1; pp. 972 - 12 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
18.01.2023
Nature Publishing Group Nature Portfolio |
Subjects | |
Online Access | Get full text |
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Summary: | FAT atypical cadherin 1 (FAT1), a transmembrane protein, is frequently mutated in various cancer types and has been described as context-dependent tumor suppressor or oncogene. The
FAT1
gene is mutated in 12–16% of T-cell acute leukemia (T-ALL) and aberrantly expressed in about 54% of T-ALL cases contrasted with absent expression in normal T-cells. Here, we characterized
FAT1
expression and profiled the methylation status from T-ALL patients. In our T-ALL cohort, 53% of patient samples were
FAT1
positive (FAT1pos) compared to only 16%
FAT1
positivity in early T-ALL patient samples. Aberrant expression of
FAT1
was strongly associated with
FAT1
promotor hypomethylation, yet a subset, mainly consisting of TLX1-driven T-ALL patient samples showed methylation-independent high
FAT1
expression. Genes correlating with
FAT1
expression revealed enrichment in WNT signaling genes representing the most enriched single pathway.
FAT1
knockdown or knockout led to impaired proliferation and downregulation of WNT pathway target genes (
CCND1
,
MYC
,
LEF1)
, while
FAT1
overexpressing conveyed a proliferative advantage. To conclude, we characterized a subtype pattern of
FAT1
gene expression in adult T-ALL patients correlating with promotor methylation status.
FAT1
dependent proliferation and WNT signaling discloses an impact on deeper understanding of T-ALL leukemogenesis as a fundament for prospective therapeutic strategies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-023-27792-0 |