Systemic mastocytosis (SM) is an incurable neoplasm characterized by abnormal accumulation of neoplastic mast cells (MC) in vascularized organs. In indolent SM, MC express several different adhesion-molecules including CD2 and CD58, and form focal tissue-aggregates, whereas in advanced SM, MC often lack CD2 and produce a more diffuse infiltration-pattern. To explore the functional role of CD2 in the pathology of SM, stable CD2+ and CD2 subclones of the human MC-leukemia cell line HMC-1 were generated and injected intraperitoneally into pfp/rag2 mice. CD2+ HMC-1 cells formed solid mastocytomas in the peritoneum and lungs, whereas CD2 cells produced diffuse infiltration. CD2+ and CD2 HMC-1 subclones all displayed the driver-mutant KIT D816V, exhibited the same growth-kinetics, and displayed identical adhesion-receptors including CD44 and selectin-ligands. To explore the mechanism of organ invasion, E- and P-selectin-deficient scid mice (scid-select) were employed. While massive HMC-1 infiltrates were detected in the lungs of control mice, infiltration was markedly reduced or absent in scid-select mice. The invasion-receptor CD44 was detectable in all MC infiltrates, with most abundant expression in the invasion-front. Together, our data show that selectins mediate organ-invasion of MC and CD2-CD58 interactions contribute to a more focal infiltration-pattern which is lost during progression to MC leukemia.