Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with high incidence and recurrence rates. Gene expression profiling has revealed that transcriptional overexpression of glioma‐associated oncogene 1 (GLI1), a vital gene in the Hedgehog (Hh) signaling pathway, occurs in poor-prognosis AML, and high levels of phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1) and AKT3 predict shorter overall survival in AML patients. In this study, we discovered that GLI1 overexpression promotes cell proliferation and reduces chemotherapy sensitivity in AML cells while knocking down GLI1 has the opposite effect. Moreover, GLI1 promoted cell cycle progression and led to elevated protein levels of cyclins and cyclin-dependent kinases (CDKs) in AML cells. By luciferase assays and co-immunoprecipitation, we demonstrated that the PI3K/AKT pathway is directly activated by GLI1. GLI1 overexpression significantly accelerates tumor growth and upregulated p-AKT, CDK4, and cyclinD3 in vivo. Notably, the GLI1 inhibitor GANT61 and the CDK4/6 inhibitor PD 0332991 had synergistic effects in promoting Ara-c sensitivity in AML cell lines and patient samples. Collectively, our data demonstrate that GLI1 reduces drug sensitivity by regulating cell cycle through the PI3K/AKT/GSK3/CDK pathway, providing a new perspective for involving GLI1 and CDK4/6 inhibitors in relapsed/refractory (RR) patient treatment.
Highlights
Acute myeloid leukemia (AML) is a hematological malignancy with poor overall clinical outcome
glioma‐associated oncogene 1 (GLI1) regulates AML cell proliferation and drug sensitivity To investigate whether the Hh and phosphoinositide 3‐kinase (PI3K)/AKT signaling pathways are dysregulated in AML-RR patients, we performed RNA-seq using pooled bone marrow samples collected from AML-RR patients (Fig. 1A)
We found that signature gene of the Hh signaling pathway e.g., GLI1, PTCH1, SMO, and the PI3K/AKT pathway e.g., phosphoinositide-3-kinase, regulatory subunit 1 (PIK3R1), AKT1, AKT2, were upregulated in AML-RR compared to AML-CR patients, indicating that both the Hh and PI3K/ AKT signaling pathways were up-regulated in AML-RR patients (Fig. 1B, C)
Summary
Acute myeloid leukemia (AML) is a hematological malignancy with poor overall clinical outcome. Chemotherapy, such as Ara-c combination chemotherapy, is the most commonly used treatment for this disease. LSCs, which give rise to leukemic blasts, are resistant to chemotherapy and responsible for disease relapse[1]. Hh binds to Ptch, while Smo transduces the Hh signal, which is mediated by glioma-associated oncogene homolog (Gli) family members (GLI1, 2, 3)[7,8]. Among these family members, GLI1 acts as both a transcriptional activator and a Hh target gene[9]. GLI1 is regarded as the most reliable indicator for Hh pathway activation[10]
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