Fusion Oncoproteins in Childhood Cancers: Potential Role in Targeted Therapy

Abstract

Cancer remains the leading cause of death from disease in children. Historically, in contrast to their adult counterparts, the causes of pediatric malignancies have remained largely unknown, with most pediatric cancers displaying low mutational burdens. Research related to molecular genetics in pediatric cancers is advancing our understanding of potential drivers of tumorigenesis and opening new opportunities for targeted therapies. One such area is fusion oncoproteins, which are a product of chromosomal rearrangements resulting in the fusion of different genes. They have been identified as oncogenic drivers in several sarcomas and leukemias. Continued advancement in the understanding of the biology of fusion oncoproteins will contribute to the discovery and development of new therapies for childhood cancers. Here we review the current scientific knowledge on fusion oncoproteins, focusing on pediatric sarcomas and hematologic cancers, and highlight the challenges and current efforts in developing drugs to target fusion oncoproteins.

CIC-DUX4 Chromatin Profiling Reveals New Epigenetic Dependencies and Actionable Therapeutic Targets in CIC-Rearranged Sarcomas

“…Chromosomal translocations often result in the formation of fusion proteins that can drive malignant transformation, leading to the emergence of various cancer types [1,2]. These aberrant proteins, also known as onco-fusion proteins, may acquire neo-morphic properties which are distinct from their parent counterparts, and frequently hijack the epigenetic machinery to induce cellular transformation from permissive precursor cells [3]. In keeping with this, the signaling and transcriptional regulatory mechanisms, as well as the oncogenic properties, controlled by the newly formed onco-fusion proteins, heavily rely on their fusion partners and originating cells [2].…”

“…While they are likely to retain DNA-binding specificity, their genome-wide occupancy, co-factor preferences, and chromatin activity can differ from their corresponding wild-type (wt) counterparts, providing each fusion protein with distinct neo-morphic properties that vary across tumor entities [4]. This type of aberrant TF-mediated tumorigenesis is mainly observed in a subset of leukemias and solid tumors, particularly sarcomas [3,5] and relies on the expression of the fusion proteins in a permissive cellular context that creates a favorable environment for their oncogenic activity [6][7][8].…”

Rapid gene fusion testing using the NanoString nCounter platform to improve pediatric leukemia diagnoses in Sub-Saharan Africa

“…The genomics of pediatric leukemias have been well-studied in high resource settings (9)(10)(11). Gene fusions are estimated to occur in >50% of pediatric leukemias (12)(13)(14)(15), with an additional 25% due to aneuploidy. The presence of a gene fusion in pediatric leukemia can be prognostic: examples include a favorable prognosis for B-acute lymphoblastic leukemia (B-ALL) with a ETV6-RUNX1 fusion or unfavorable prognosis of an acute myeloid leukemia (AML) patient with CBFA2T3-GLIS1 fusion.…”

FusOn-pLM: A Fusion Oncoprotein-Specific Language Model via Focused Probabilistic Masking

“…The resulting mutants contain unrelated functional domains connected by long regions of disorder. This flexible configuration promotes constitutive activation or aberrant regulation of the fusion proteins, driving oncogenic transformation and tumor development [ Angione et al, 2021 ]. Thousands of unique fusion oncoproteins have been discovered by sequencing patient tumors, and several common culprits such as EWS::FLI1 in Ewing’s sarcoma [ Delattre et al, 1992 ], PAX3::FOXO1 in alveolar rhabdomyosarcoma (ARMS) [ Linardic, 2008 ], SS18::SSX1 in synovial sarcoma [ McBride et al, 2018 ], and EML4::ALK proteins in non-small-cell lung cancer [ Soda et al, 2007 ] are well characterized in the literature.…”