MYLIP-dependent ubiquitination and degradation of LDLR in acute myeloid leukemia and MAPK signaling

Acute myeloid leukemia (AML) is a hematologic malignancy that necessitates the identification of new therapeutic targets. Recently, the low-density lipoprotein receptor (LDLR) has been linked to an unfavorable prognosis in AML. LDLR plays a crucial role in various signaling pathways, including the MAPK signaling pathway. Our data show high LDLR expression in the AML cell lines THP-1 and NB4. Knockdown of LDLR using shRNA reduced AML cell proliferation, induced apoptosis, and led to S-phase cell accumulation, accompanied by modulation of the MAPK pathway. Additionally, myosin regulatory light chain-interacting protein (MYLIP) is expressed at low levels in AML and regulates LDLR. Overexpression of MYLIP downregulated LDLR expression, accompanied by an influence on the MAPK signaling pathway. Functionally, MYLIP overexpression decreased AML cell proliferation, increased apoptosis, and potentially delayed S-phase progression. These findings suggest that MYLIP and LDLR may regulate AML cell expansion, potentially through effects on the MAPK pathway. Furthermore, the p38-MAPK activator PCS reversed the inhibitory effect of LDLR knockdown and MYLIP overexpression on cell proliferation. Consequently, targeting LDLR could be a promising approach for AML treatment.