Only STAT5B plays a distinct and dominant role in self-renewal of HSCs and LSCs. Left panel: receptor engagement predominantly activates STAT5B in HSCs. STAT5B, in turn, selectively activates a set of “quiescence” genes that drive self-renewal and quiescence of HSCs. One of the STAT5B target genes is CD9. Right panel: the dominant role of STAT5B extends to LSCs. Oncogene stimulation predominantly activates STAT5B in LSCs. Subsequently, STAT5B selectively activates a set of “quiescence” genes that drive self-renewal of LSCs. CD9 expression levels are higher in LSCs than in HSCs. Blocking CD9 by antibodies can induce differentiation and apoptosis in STAT5B-driven LSCs, leading to their eradication. Professional illustration by Somersault18:24.