Targeting the origins of multiple myeloma along hematopoietic stem cell lymphoid lineage differentiation

The initiation and progression of multiple myeloma (MM) are intricate processes, and a critical challenge lies in understanding the mechanisms of malignant transformation in MM-initiating cells (MICs) and their driver genes. In this study, we used single-cell sequencing and genetic tracer analysis at each developmental stage, from hematopoietic stem cells to lymphoid lineage differentiation, to identify abnormal differentiation stages in patients with MM. We found that chromosome 1q amplification (1q^Amp) originated from a specific subgroup of B cells, whereas chromosome 17p deletion occurred at the plasma cell stage. 1q^Amp was present in CD24^-FCRL5⁺ B cell subgroups and initiated B cell transformation into malignant plasma cells by enhancing B cell proliferation and promoting plasma cell differentiation in vitro and in vivo. FCRL5 facilitated B cell differentiation into malignant plasma cells through its interaction with the IRF4/SPI1 complex. The use of targeted FCRL5 CAR T cells in patients with relapsed or refractory MM (RRMM) showed promising safety and efficacy. Together, our work identified genetic events linked to the initiation and malignant transformation of MM along the B cell lineage. These findings form the foundation for identifying potential therapeutic strategies for patients with RRMM by targeting MICs and their driving oncogenes.