Epigenetic regulator BMI1 promotes alveolar rhabdomyosarcoma proliferation and constitutes a novel therapeutic target.

Cara E Shields,Shiv A Patel,Corinne M Linardic,Komal S Rathi,Daniel Martinez,Karmella A Haynes,Selma M Cuya‐Smith,Dongdong Chen,John M Maris,Kristianne M Oristian,Robert W Schnepp,Sarah K Chappell,Jennifer Pogoriler,Sindhu Potlapalli

doi:10.1002/1878-0261.12914

Abstract

Rhabdomyosarcoma (RMS) is an aggressive pediatric soft tissue sarcoma. There are two main subtypes of RMS, alveolar rhabdomyosarcoma (ARMS) and embryonal rhabdomyosarcoma. ARMS typically encompasses fusion‐positive rhabdomyosarcoma, which expresses either PAX3‐FOXO1 or PAX7‐FOXO1 fusion proteins. There are no targeted therapies for ARMS; however, recent studies have begun to illustrate the cooperation between epigenetic proteins and the PAX3‐FOXO1 fusion, indicating that epigenetic proteins may serve as targets in ARMS. Here, we investigate the contribution of BMI1, given the established role of this epigenetic regulator in sustaining aggression in cancer. We determined that BMI1 is expressed across ARMS tumors, patient‐derived xenografts, and cell lines. We depleted BMI1 using RNAi and inhibitors (PTC‐209 and PTC‐028) and found that this leads to a decrease in cell growth/increase in apoptosis in vitro, and delays tumor growth in vivo. Our data suggest that BMI1 inhibition activates the Hippo pathway via phosphorylation of LATS1/2 and subsequent reduction in YAP levels and YAP/TAZ target genes. These results identify BMI1 as a potential therapeutic vulnerability in ARMS and warrant further investigation of BMI1 in ARMS and other sarcomas.

Highlights

Rhabdomyosarcoma (RMS) is a tumor of developing skeletal myoblast-like cells that primarily afflicts children.[1]
We found that B lymphoma Mo-MLV insertion region 1 (BMI1) mRNA levels are highly expressed in Fusion-positive rhabdomyosarcoma (FP-RMS) compared to normal tissues (Fig. 1B)
We focused on Hippo signaling as BMI1 has been reported to interact with the Yes-Associated Protein (YAP) in Ewing sarcoma.[22]

Summary

Introduction

Rhabdomyosarcoma (RMS) is a tumor of developing skeletal myoblast-like cells that primarily afflicts children.[1] There are two main subtypes of RMS, fusion positive (FPRMS) and fusion negative (FN-RMS), which are classified by the presence or absence of the PAX-FOXO1 fusion protein.[1,2] FP-RMS typically encompasses alveolar rhabdomyosarcoma (ARMS), with FN-RMS emerging as the preferred term for embryonal rhabdomyosarcoma (ERMS).[1] These subtypes are based upon histological observations, but as we move more toward defining cancers molecularly, utilizing fusion status is more useful and accurate.[1] FP-RMS has a worse outcome compared to FNRMS, with an overall survival rate of below 30%, and an even more dire prognosis for patients with metastatic disease.[3] Currently, the standard of care is multimodal and intensive, consisting of multiagent chemotherapy, radiation, and surgery.[4,5] Given the substantial morbidity and mortality of FP-RMS, there is a need for novel, translatable treatment options

Methods

Results

Conclusion