WT1 together with RUNX1::RUNX1T1 targets DUSP6 to dampen ERK activity in acute myeloid leukaemia.

Summary Wilms' tumour 1 (WT1) can function as an oncogene or a tumour suppressor. Our previous clinical cohort studies showed that low <italic>WT1</italic> expression at diagnosis independently predicted poor outcomes in acute myeloid leukaemia (AML) with <italic>RUNX1::RUNX1T1</italic>, whereas it had an opposite role in AML with non‐favourable cytogenetic risk (<italic>RUNX1::RUNX1T1</italic>‐deficient). The molecular mechanism by which RUNX1::RUNX1T1 affects the prognostic significance of <italic>WT1</italic> in AML remains unknown. In the present study, first we validated the prognostic significance of <italic>WT1</italic> 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 <italic>RUNX1::RUNX1T1</italic>. 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 <italic>DUSP6</italic> to dampen extracellular signal‐regulated kinase (ERK) activity. When <italic>RUNX1::RUNX1T1</italic>‐deficient, WT1 can activate the mitogen‐activated extracellular signal‐regulated kinase/ERK axis but not through targeting <italic>DUSP6</italic>. 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 <italic>WT1</italic> expression in AML patients. [ABSTRACT FROM AUTHOR]