CD47 promotes myeloma cell growth through JAK-STAT3/MYC signalling and is targetable by ruxolitinib.
Cluster of differentiation 47 (CD47), a 'don't eat me' immune checkpoint receptor, is frequently overexpressed on multiple myeloma (MM) cells and contributes to immune evasion. While its immune regulatory function is well established, the intrinsic oncogenic role of CD47 remains poorly understood. Here, we demonstrate for the first time that CD47 intrinsically promotes myeloma cell proliferation and survival by activating the JAK/STAT3-MYC (Janus kinase/signal transducer and activator of transcription 3 - MYC) signalling axis. CD47 overexpression increased cell growth, accelerated G1-M-cell cycle progression and promoted anchorage-independent colony formation, accompanied by elevated phosphorylation of STAT3 and upregulation of MYC, whereas CD47 knockdown produced the opposite effects. Transcriptomic analysis of patient datasets revealed that high CD47 expression was associated with enrichment of the JAK-STAT3 and MYC pathways, and CD47 levels positively correlated with STAT3 and MYC expression, suggesting a potential regulatory interplay among these molecules. Pharmacological inhibition using the JAK1/2 inhibitor ruxolitinib (Rux) decreased cell viability, induced apoptosis and suppressed STAT3 and MYC signalling. Moreover, Rux synergized with bortezomib in myeloma cell lines and primary patient samples but spared normal cells. Collectively, these findings identify CD47 as an oncogenic driver with an intrinsic signalling function in MM and highlight the CD47-STAT3-MYC axis as a promising therapeutic target.