In vitro studies show that BCR/ABL-expressing hematopoietic cells exhibit altered adhesion properties. No in vivo studies show whether the altered adhesion properties affect BCR/ABL leukemo-genesis. Using mice with homozygous inactivation of genes encoding the 2 adhesion molecules P-selectin and intercellular adhesion molecule-1 (ICAM1), we show that the mutant mice develop BCR/ABL-induced chronic myeloid leukemia (CML)-like leukemia at a significantly faster rate than do wild-type (WT) mice. Lack of P-selectin and ICAM1 did not have a significant effect on the development of B-cell acute lymphoblastic leukemia (BALL) induced by BCR/ABL. Using mice deficient for P-selectin or ICAM1 alone, we show that P-selectin plays a major role in the acceleration of CML-like leukemia. Lack of P-selectin resulted in early release of BCR/ABL-expressing myeloid progenitors from bone marrow, appearing to alter the biologic properties of leukemic cells rather than their growth rate by increasing their homing to the lungs, causing fatal lung hemorrhages. These results indicate that adhesion of BCR/ABL-expressing myeloid progenitors to marrow stroma through P-selectin and ICAM1 play an inhibitory role in the development of CML-like disease, suggesting that improvement of adhesion between BCR/ABL-expressing myeloid progenitor cells and bone marrow stroma may be of therapeutic value for human CML. (Blood. 2004;104:2163-2171)