Imatinib restores expression of CD62L in BCR-ABL-positive cells

Abstract

Chronic myelogenous leukemia (CML) is characterized by aberrant trafficking of malignant hematopoietic progenitor cells in the peripheral blood. Expression of the cell adhesion molecule CD62L was reported to be significantly lower in CML patients than in normal controls. We studied whether the transcription of CD62L in CML cells is dependent on the activity of the BCR-ABL tyrosine kinase. Following addition of the Abelson (ABL) tyrosine kinase inhibitor imatinib (formerly STI571) to two BCR-ABL-positive cell lines (BV173, SD-1), we observed a dose-dependent increase in CD62L RNA levels of up to 45-fold by a quantitative, real-time polymerase chain reaction and an increase in the amount of cell surface-bound CD62L of up to 18-fold by quantitative flow cytometry, respectively. These data are validated by an increased CD62L expression in the bone marrow of patients (n=6) with advanced CML who received imatinib. Restoration of defective cell adhesion mediated via the CD62L pathway may be one mechanism of action of imatinib in BCR-ABL-positive leukemias.

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach

“…24 The low levels of expression of adhesion molecules detected in imatinib-resistant patients could be related to their inability to respond to imatinib. Although it seems that adhesion defects in CML may be tyrosine-kinase-independent, 25 restoration of celladhesion molecules may be a mechanism of action of imatinib, as has been demonstrated in in vitro studies by Fruehauf et al 26 for the adhesion molecule L-selectin (CD62L). Likewise, Pelletier et al 27 have suggested that improvement of adhesion between BCR-ABL-expressing myeloid progenitor cells and bone marrow stroma may be of therapeutic value for human CML.…”

BCR/ABL-mediated downregulation of genes implicated in cell adhesion and motility leads to impaired migration toward CCR7 ligands CCL19 and CCL21 in primary BCR/ABL-positive cells

“…[31][32][33][34][35][36][37] Decreased mRNA levels for L-selectin in p210 UCB and early CP CML CD34 þ cells is consistent with published reports demonstrating decreased expression of L-selectin on BM CD34 þ cells derived from CML patients. [38][39][40] We observed populations of CD34 þ cells with higher and lower levels of L-selectin protein expression in primary cells as well as in the UCB transduction model possibly based on subpopulations. Hence, it is possible that the decreased levels of ICAM1 and L-selectin in CML samples is due to skewing of the population away from the population expressing higher numbers of these adhesion molecules.…”

Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche

“…Coexpression of E/L-selectin rescued the leukemogenic defect of L-selectin-deficient BM, with 100% of recipient mice developing CML-like leukemia with the same latency as recipients of WT BM ( Figure 6A-B), whereas coexpression of E/Lselectin with BCR-ABL1 in WT BM did not significantly alter the CML-like disease (data not shown). As the chimeric E/L-selectin is resistant to shedding induced by BCR-ABL1, 53 malignant myeloid cells from these leukemic mice expressed human E/L-selectin on their cell surface ( Figure 6D). Importantly, the engraftment defect of the L-selectin-deficient leukemic stem cells was also rescued by coexpression of the stabilized E/L-selectin chimera ( Figure 6E), with an increase in the clonality of the leukemia from 1.2 6 0.4 proviral clones per recipient of L-selectin KO BM to 4.6 6 3.3 clones expressing E/L-selectin (P 5 .028, Student t test).…”