A working model depicting a role for MS4A3 in regulating CML LSC differentiation and TKI sensitivity, via modulating common βc receptor endocytosis and signaling. Left: in BCR-ABL1⁺ CML LSCs, BCR-ABL signaling (a), DNA and histone methylation (me) (b), as well as the MECOM/CEBPE axis (c) transcriptionally downregulate MS4A3, that encodes a tetraspan membrane protein. Low MS4A3 levels contribute to LSC quiescence, TKI resistance, and differentiation block in BP-CML. Right: MS4A3 levels are high in TKI-sensitive CML, or when exogenously delivered, they bind to the common βc for the GM-CSF and IL-3 receptors in the cell membrane, promote receptor endocytosis and activation of ERK and STAT5, thereby enhancing LSC differentiation.