Analysis of CD74 Occurrence in Oncogenic Fusion Proteins

Abstract

CD74 is a type II cell surface receptor found to be highly expressed in several hematological and solid cancers, due to its ability to activate pathways associated with tumor cell survival and proliferation. Over the past 16 years, CD74 has emerged as a commonly detected fusion partner in multiple oncogenic fusion proteins. Studies have found CD74 fusion proteins in a range of cancers, including lung adenocarcinoma, inflammatory breast cancer, and pediatric acute lymphoblastic leukemia. To date, there are five known CD74 fusion proteins, CD74-ROS1, CD74-NTRK1, CD74-NRG1, CD74-NRG2α, and CD74-PDGFRB, with a total of 16 different variants, each with unique genetic signatures. Importantly, the occurrence of CD74 in the formation of fusion proteins has not been well explored despite the fact that ROS1 and NRG1 families utilize CD74 as the primary partner for the formation of oncogenic fusions. Fusion proteins known to be oncogenic drivers, including those of CD74, are typically detected and targeted after standard chemotherapeutic plans fail and the disease relapses. The analysis reported herein provides insights into the early intervention of CD74 fusions and highlights the need for improved routine assessment methods so that targeted therapies can be applied while they are most effective.

Keywords: CD74-NRG1; CD74-NRG2α; CD74-NTRK1; CD74-PDGFRB; CD74-ROS1; cancer; cluster of differentiation 74 (CD74); fusion gene; oncogenic fusion protein.

Figure 1

The CD74 isoforms P41 (280 aa—bottom left), P35 (232 aa—top left), P33 (216 aa—top right), and P43 (296 aa—bottom right) depicted on the cell surface of a healthy human cell. Experimentally resolved structural fragments of CD74 are illustrated in boxes along with their corresponding PDB numbers. The predicted structure of P43, produced by AlphaFold Protein Structure Database, is also provided [50,51]; Accension AF-P04233. The size of each domain shown in the figure is drawn with no scale. Light orange color denotes the transmembrane domain. IC: Intracellular, EC: extracellular, CLIP: class II-associated invariant chain peptide, TM: transmembrane domain, TD: trimerization domain, E6B: exon 6b, EXT: N-terminal extension.

Figure 2

CD74 oncogenic fusions. From left to right, CD74-NRG2α, CD74-NTRK1, CD74-ROS1, CD74-PDGFRB, and CD74-NRG1 are depicted on the membrane of a cancer cell. The CD74 segments participating in the formation of these fusions are enclosed within the dashed rectangles. For each fusion, the functional domain (EGF and KD) known to contribute to the protein’s oncogenic activity is illustrated. In all cases, this domain is derived from the protein partner of CD74. The size of each domain shown in the figure is drawn with no scale. IC: Intracellular, TM: transmembrane domain, EC: extracellular, EGF: epidermal growth factor-like domain, KD: kinase domain.

Figure 3

Timeline for the identification of CD74 fusions. The original study, gender of the patient, and type of cancer are also reported. CD74-ROS1 [30], CD74-NTRK1 [31], CD74-NRG1 [32], CD74-NRG2α [33], and CD74-PDGFRB are displayed in chronological order [34]. Of note, the gender of the CD74-NTRK1 patient was not reported in the original study.