Targeting WNK1 Releases Differentiation Block in Acute Myeloid Leukemia

Abstract

Impaired differentiation is a hallmark of Acute Myeloid Leukemia (AML). Current differentiation therapies benefit only a small subset of AML patients, leaving a substantial gap in care for other subtypes. Identifying novel molecular drivers of maturation arrest is critical to expand differentiation induction to a broader range of AML patients. This study addresses this unmet clinical need, by identifying With-no-Lysine(K) kinase 1 (WNK1) as a novel regulator of AML differentiation arrest. We show that WNK1 expression and activity are elevated in AML patients. WNK1 inhibition induced differentiation accompanied by decreased growth and survival of AML cell lines and patient cells. It also inhibited self-renewal of AML patient cells in vitro and elicited significant anti-tumor activity in vivo in mouse models. Mechanistically, WNK1 inhibition derepressed the MEK-ERK-C/EBP{beta} signaling axis and increased the expression of myeloid differentiation genes. Our findings reveal a novel role of WNK1 in promoting AML through differentiation arrest, posing WNK1 inhibition as a potential approach for AML differentiation therapy.