Analysis of gene expression change between THP-1 SC and THP-1 shPLAC8

Acute myeloid leukemia (AML) frequently relapses after chemotherapy, highlighting the need to understand how leukemic cell proliferation relates to treatment susceptibility. Here, we investigated the roles of placenta-specific protein 8 (PLAC8) in AML cell-cycle regulation and cytarabine response. Analyses of bulk and single-cell transcriptomic datasets identified high PLAC8 expression in AML, particularly in early hematopoietic and myeloid populations. PLAC8 depletion increased the G0/G1 fraction, reduced proliferation, and decreased CDK4 and CCND1 expression, while having limited effects on the differentiation phenotypes examined. MYC silencing reduced PLAC8 expression, and chromatin immunoprecipitation detected MYC occupancy at the PLAC8 locus. Conversely, PLAC8 depletion reduced MYC occupancy at the CDK4 promoter without decreasing MYC expression. Coimmunoprecipitation detected an association between overexpressed MYC and PLAC8, supporting a model in which PLAC8 contributes to MYC-associated cell-cycle regulation. Despite its association with proliferation, lower PLAC8 expression was associated with shorter overall survival in two AML cohorts and was observed at relapse in paired samples from two patients. PLAC8 silencing reduced cytarabine-induced apoptosis and increased the cytarabine half-maximal inhibitory concentration in THP-1 cells. Both PLAC8-silenced and cytarabine-resistant cells exhibited increased AXL expression. Combining cytarabine with the AXL inhibitor bemcentinib enhanced apoptosis and produced Bliss synergy in cell-viability assays. These findings identify distinct roles for PLAC8 in AML proliferation and cytarabine sensitivity and provide a rationale for investigating AXL inhibition in PLAC8-low AML.