WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia
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| Natura: | Artículo Open Access |
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Wiley
2024
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| _version_ | 1867011567139160064 |
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| author | Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin |
| author_facet | Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin |
| collection | Wiley Open Access |
| contents | WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin British Journal of Haematology SummaryWilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non‐favourable cytogenetic risk (RUNX1::RUNX1T1‐deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co‐factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal‐regulated kinase (ERK) activity. When RUNX1::RUNX1T1‐deficient, WT1 can activate the mitogen‐activated extracellular signal‐regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients. 10.1111/bjh.19721 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1111/bjh.19721 |
| format | Artículo Open Access |
| id | wiley_oa_10_1111_bjh_19721 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin British Journal of Haematology WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia Nan Xu Feng‐Ting Dao Zong‐Yan Shi Kai Sun Ya‐Zhen Qin British Journal of Haematology SummaryWilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low WT1 expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with RUNX1::RUNX1T1, whereas it had an opposite role in AML with non‐favourable cytogenetic risk (RUNX1::RUNX1T1‐deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of WT1 in AML remains unknown. In the present study, first we validated the prognostic significance of WT1 expression in AML. Then by using the established transfected cell lines and xenograft tumour model, we found that WT1 suppresses proliferation and enhances effect of cytarabine in RUNX1::RUNX1T1(+) AML but has opposite functions in AML cells without RUNX1::RUNX1T1. Furthermore, as a transcription factor, WT1 physically interacts with RUNX1::RUNX1T1 and acts as a co‐factor together with RUNX1::RUNX1T1 to activate the expression of its target gene DUSP6 to dampen extracellular signal‐regulated kinase (ERK) activity. When RUNX1::RUNX1T1‐deficient, WT1 can activate the mitogen‐activated extracellular signal‐regulated kinase/ERK axis but not through targeting DUSP6. These results provide a mechanism by which WT1 together with RUNX1::RUNX1T1 suppresses cell proliferation through WT1/DUSP6/ERK axis in AML. The current study provides an explanation for the controversial prognostic significance of WT1 expression in AML patients. 10.1111/bjh.19721 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia |
| topic | British Journal of Haematology |
| url | https://onlinelibrary.wiley.com/doi/10.1111/bjh.19721 |