Tumor-derived CD84 promotes growth of acute myeloid leukemia cells via regulating nonhomologous DNA end-joining pathway

CD84, a member of the signaling lymphocyte activation molecule immunoglobulin superfamily, has been identified as playing a significant role in regulating various immune cell activities. However, its intrinsic role in cancer cells remains largely unknown. We aim to explore the direct role of CD84 in acute myeloid leukemia (AML) progression and to clarify the underlying molecular mechanisms involved in nonhomologous end-joining (NHEJ) repair. Herein, we found that CD84 is frequently upregulated in various types of AML and leukemia initiation cells (LICs)-enriched cells. Knockdown or blocking of CD84 significantly inhibits the growth and induces the apoptosis of AML cells. Moreover, knockdown of CD84 significantly delays AML progression and prolongs the survival of the xenografted mice in vivo. Mechanistically, CD84 promotes the expression of NHEJ core factors by recruiting SAP and activating the AKT signaling pathway. Knockdown of CD84 inhibits NHEJ repair in AML cells via regulating the expression of NHEJ core factors, including PRKDC, LIG4, XRCC5, and DCLRE1C. Subsequently, this leads to double-strand breaks accumulation and cell apoptosis. Importantly, CD84 is required for the proliferation and self-renewal of human LICs. In conclusion, CD84 plays important roles in AML growth and progression through promoting NHEJ repair. Targeting CD84 may be a potential approach for inhibiting AML development and eliminating LICs.