Discovery of the Oncogenic Parp1, a Target of bcr-abl and a Potential Therapeutic, in mir-181a/PPFIA1 Signaling Pathway

Guiping Huang,Zhao Yin,Chunming Gu,Jia Fei,Yumin Li,Juhua Yang,Xuejiao Zhu,Yanjun Liu

doi:10.1016/j.omtn.2019.01.015

Guiping Huang, Zhao Yin + Show 6 more

Open Access

https://doi.org/10.1016/j.omtn.2019.01.015

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Abstract

miR-181a is downregulated in leukemia and affects its progression, drug resistance, and prognosis. However, the exact mechanism of its targets in leukemia, particularly in chronic myelogenous leukemia (CML), has not previously been established. Here, we use a multi-omics approach to demonstrate that protein tyrosine phosphatase, receptor type, f polypeptide, leukocyte common antigen (LAR) interacting protein (liprin), alpha 1 (PPFIA1) is a direct target for miR-181a in CML. Phospho-array assay shows that multiple phosphorylated proteins, particularly KIT signaling molecules, were downregulated in PPFIA1 inhibition. Additionally, PPFIA1 bound PARP1, a common molecule downstream of both PPFIA1 and BCR/ABL, to upregulate KIT protein through activation of nuclear factor kappa B (NF-κB)-P65 expression. Targeted inhibition of PPFIA1 and PARP1 downregulated c-KIT level, inhibited CML cell growth, and prolonged mouse survival. Overall, we report a critical regulatory miR-181a/PPFIA1/PARP1/NF-κB-P65/KIT axis in CML, and our preclinical study supports that targeted PPFIA1 and PARP1 may serve as a potential CML therapy.

Highlights

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder with approximately 1–2 people per 100,000 population, and accounts for 15% of all leukemia in adults.[1]
Transwell assays showed that the invasion ability of chronic myelogenous leukemia (CML) cells was significantly reduced by treatment with either miR-181a mimic or PPFIA1 small interfering RNA (siRNA) (Figure 2B)
The colony-forming ability of K562 cells transfected with miR-181a mimic or PPFIA1 siRNA was significantly reduced compared with cells transfected with the negative control (NC) group (p < 0.05) (Figure 2C)

Summary

Introduction

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder with approximately 1–2 people per 100,000 population, and accounts for 15% of all leukemia in adults.[1] The Philadelphia chromosome (Ph) is a specific genetic abnormality with a t(9,22) reciprocal chromosomal translocation in leukemia cells ( CML cells). IM shows remarkable therapeutic effect as a component of frontline treatment regimens for CML.[3] The capacity of IM to inhibit non-BCR/ABL1 targets has expanded its use to treatment of malignancies driven by KIT mutations, which has been implicated in CML pathogenesis. Dual inhibition of BCR/ABL and KIT is required for suppression of mature CML progenitors, and the stem cell factor (SCF)/KIT pathway must be inhibited to enable apoptosis induced by BCR/ABL inhibitors in CML cells.[4,5]

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